127 results on '"Elena Cichero"'
Search Results
52. Targeting species-specific trace amine-associated receptor 1 ligands: to date perspective of the rational drug design process
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Elena Cichero and Michele Tonelli
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0301 basic medicine ,Pharmacology ,Binding Sites ,Drug discovery ,Druggability ,Drug design ,Computational biology ,Biology ,Ligands ,Trace amine associated receptor 1 ,Receptors, G-Protein-Coupled ,Molecular Docking Simulation ,Structure-Activity Relationship ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Docking (molecular) ,Drug Design ,Drug Discovery ,Thyronines ,Animals ,Humans ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
G-protein-coupled receptors represent main targets of several clinically relevant drugs, playing nowadays a leading part for further drug discovery process. Trace amine-associated receptor's family (TAARs) assumed an intriguing role as druggable target in medicinal chemistry, being TAAR1 the most investigated. Indeed, related ligands proved to be intertwined in several circuits involved in pathological pathways or therapeutic routes. Herein, we highlight relevant efforts in the search of novel agonists, focusing on responsiveness featured by different chemotypes toward rodent and human TAAR1, in order to explore species-specificity preferences. We also discuss the main strategies guiding so far the design of new TAAR1 agonists, giving a perspective of the structure-based methodologies aimed at deriving new insights for more potent and selective derivatives.
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- 2017
53. Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands
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Michele Tonelli, Livio Brasili, Paola Fossa, Sara Guariento, Claudia Sorbi, Silvia Franchini, and Elena Cichero
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Pharmacology ,CoMFA ,010405 organic chemistry ,Stereochemistry ,Drug discovery ,Ligand ,Chemistry ,lcsh:RM1-950 ,General Medicine ,Computational biology ,5HT1A-ligands ,010402 general chemistry ,Adrenoreceptor ,01 natural sciences ,Partial agonist ,0104 chemical sciences ,lcsh:Therapeutics. Pharmacology ,Drug Discovery ,Selectivity ,CoMSIA ,3D-QSAR - Abstract
The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands.
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- 2017
54. New arylsparteine derivatives as positive inotropic drugs
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Paola Dorigo, Michele Tonelli, Vito Boido, Marcella Ercoli, Fabio Sparatore, Bruno Tasso, Guglielmina Froldi, Paola Fossa, Federica Novelli, and Elena Cichero
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Chronotropic ,Inotrope ,Male ,Cardiotonic Agents ,Digoxin ,Proton Magnetic Resonance Spectroscopy ,2-aryl-2-dehydrosparteines ,positive inotropic agents ,Guinea Pigs ,Sparteine ,Drug Evaluation, Preclinical ,030204 cardiovascular system & hematology ,Pharmacology ,In Vitro Techniques ,01 natural sciences ,Lupin alkaloids ,03 medical and health sciences ,Mice ,0302 clinical medicine ,2-arylsparteines ,Positive inotropic agents ,Animals ,Carbon-13 Magnetic Resonance Spectroscopy ,Molecular Docking Simulation ,Rats ,Drug Discovery3003 Pharmaceutical Science ,Drug Discovery ,medicine ,010405 organic chemistry ,Chemistry ,Alkaloid ,lcsh:RM1-950 ,General Medicine ,Preclinical ,0104 chemical sciences ,lcsh:Therapeutics. Pharmacology ,Inotropism ,Toxicity ,Drug Evaluation ,Milrinone ,medicine.drug ,Research Article - Abstract
Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an Emax of 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having Emax of 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.
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- 2017
55. New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach
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Monica Casale, Enrico Millo, Nara Liessi, Michele Tonelli, Giada Righetti, Paola Fossa, Elena Cichero, and Nicoletta Pedemonte
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Quantitative structure–activity relationship ,pharmacophore analyses ,lcsh:Medicine ,lcsh:RS1-441 ,Pharmaceutical Science ,Computational biology ,VX-770 ,Article ,lcsh:Pharmacy and materia medica ,Ivacaftor ,03 medical and health sciences ,0302 clinical medicine ,CFTR modulator ,CFTR potentiators ,F508del CFTR ,Molecular docking ,Pharmacophore analyses ,Drug Discovery ,medicine ,F508del cftr ,CFTR Potentiator ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,lcsh:R ,molecular docking ,Potentiator ,Cystic fibrosis transmembrane conductance regulator ,Mechanism of action ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,medicine.symptom ,Pharmacophore ,medicine.drug - Abstract
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and &pi, &ndash, &pi, stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators.
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- 2020
56. Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1
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Emilia Bellone, Simonetta Verdiani, Vincent Timmerman, Monica Bandettini di Poggio, Marco Barberis, Adriano Chiò, Vicky De Winter, Simona Capponi, Paola Mandich, Elias Adriaenssens, Paola Origone, Elena Cichero, Alessandro Geroldi, Paola Fossa, and Thomas Geuens
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0301 basic medicine ,Candidate gene ,HSP27 Heat-Shock Proteins ,Biology ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,Chaperone activity ,HSPB1 ,Molecular modelling ,SALS ,Genetics ,Genetics (clinical) ,0302 clinical medicine ,Mutant protein ,medicine ,Humans ,Genetic Predisposition to Disease ,Amyotrophic lateral sclerosis ,Heat-Shock Proteins ,Research Articles ,Aged ,Mutation ,Amyotrophic Lateral Sclerosis ,Protein turnover ,Middle Aged ,Motor neuron ,medicine.disease ,Phenotype ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Italy ,Female ,Human medicine ,Protein Multimerization ,030217 neurology & neurosurgery ,Molecular Chaperones ,Research Article - Abstract
Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.
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- 2016
57. Impaired Chaperone Activity of Human Heat Shock Protein Hsp27 Site-Specifically Modified with Argpyrimidine
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Maria Matveenko, Christian F. W. Becker, Elena Cichero, and Paola Fossa
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Ornithine ,0301 basic medicine ,Spectrometry, Mass, Electrospray Ionization ,HSP27 Heat-Shock Proteins ,biological activity ,chaperone proteins ,010402 general chemistry ,01 natural sciences ,Protein Structure, Secondary ,Catalysis ,argpyrimidine ,protein modifications ,protein semisynthesis ,03 medical and health sciences ,Residue (chemistry) ,Hsp27 ,Heat shock protein ,Humans ,Amino Acid Sequence ,Peptide sequence ,Protein secondary structure ,Heat-Shock Proteins ,biology ,Chemistry ,010405 organic chemistry ,Circular Dichroism ,Biological activity ,General Chemistry ,General Medicine ,Semisynthesis ,0104 chemical sciences ,Pyrimidines ,030104 developmental biology ,Biochemistry ,Biophysics ,biology.protein ,Spectrophotometry, Ultraviolet ,Protein Processing, Post-Translational ,Molecular Chaperones - Abstract
Non-enzymatic posttranslational modifications (nPTMs) affect at least ∼30 % of human proteins, but our understanding of their impact on protein structure and function is limited. Studies of nPTMs are difficult because many modifications are not included in common chemical libraries or protein expression systems and should be introduced site-specifically. Herein, we probed the effect of the nPTM argpyrimidine on the structure and function of human protein Hsp27, which acquires argpyrimidine at residue 188 in vivo. We developed a synthetic approach to an argpyrimidine building block, which we then incorporated at position 188 of Hsp27 through protein semisynthesis. This modification did not affect the protein secondary structure, but perturbed the oligomeric assembly and impaired chaperone activity. Our work demonstrates that protein function can be altered by a single nPTM and opens up a new area of investigation only accessible by methods that allow site-selective protein modification.
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- 2016
58. Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties
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Valeria Deiana, Eduardo Muñoz, Gérard Aimé Pinna, Javier Fernández-Ruiz, Moisés García-Arencibia, María Gómez-Cañas, Paola Fossa, Battistina Asproni, Francesco Deligia, M. Ruth Pazos, Gabriele Murineddu, and Elena Cichero
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0301 basic medicine ,Stereochemistry ,Substituent ,Pyrazole ,Ligands ,Tricyclic pyrazoles, Synthesis, Cannabinoid receptors, CB2 antagonism, Molecular modelling ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,Synthesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Cannabinoid receptor type 2 ,Humans ,Inverse agonist ,Structure–activity relationship ,Cannabinoid receptors ,Pharmacology ,chemistry.chemical_classification ,Indazole ,Organic Chemistry ,Antagonist ,General Medicine ,CB2 antagonism ,Tricyclic pyrazoles ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Pyrazoles ,lipids (amino acids, peptides, and proteins) ,Molecular modelling ,030217 neurology & neurosurgery ,Tricyclic - Abstract
Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl or a cyclohexyl substituent were designed and synthesized to evaluate the influence of these structural modifications towards CB1 and CB2 receptor affinities. Among these derivatives, compound 15 (6-cyclopropyl-1-(2,4-dichlorophenyl)-N-(adamantan-1-yl)-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide) showed the highest CB2 receptor affinity (Ki = 4 nM) and remarkable selectivity (KiCB1/KiCB2 = 2232), whereas a similar affinity, within the nM range, was seen for the fenchyl derivative (compound 10: Ki = 6 nM), for the bornyl analogue (compound 14: Ki = 38 nM) and, to a lesser extent, for the aminopiperidine derivative (compound 6: Ki = 69 nM). Compounds 10 and 14 were also highly selective for the CB2 receptor (KiCB1/KiCB2 > 1000), whereas compound 6 was relatively selective (KiCB1/KiCB2 = 27). The four compounds were also subjected to GTPγS binding analysis showing antagonist/inverse agonist properties (IC50 for compound 14 = 27 nM, for 15 = 51 nM, for 10 = 80 nM and for 6 = 294 nM), and this activity was confirmed for the three more active compounds in a CB2 receptor-specific in vitro bioassay consisting in the quantification of prostaglandin E2 release by LPS-stimulated BV2 cells, in the presence and absence of WIN55,212-2 and/or the investigated compounds. Modelling studies were also conducted with the four compounds, which conformed with the structural requirements stated for the binding of antagonist compounds to the human CB2 receptor.
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- 2016
59. A homology modelling-driven study leading to the discovery of the first mouse trace amine-associated receptor 5 (TAAR5) antagonists
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Paola Fossa, Elena Cichero, Michele Tonelli, Stefano Espinoza, Silvia Franchini, Andrey S. Gerasimov, Livio Brasili, Raul R. Gainetdinov, and Claudia Sorbi
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0301 basic medicine ,Pharmacology ,Virtual screening ,Chemistry ,Organic Chemistry ,Pharmaceutical Science ,Receptor type ,Biochemistry ,Combinatorial chemistry ,Homology (biology) ,03 medical and health sciences ,TAAR5 ,030104 developmental biology ,Drug Discovery ,Molecular Medicine ,Moiety ,Homology modeling ,Trace amine-associated receptor - Abstract
Several recent studies have focused on a detailed analysis of the trace amine-associated receptor type 5 (TAAR5) pharmacology, up to now revealing only a limited number of species-specific ligands, which are also active towards other TAAR receptors. In this context, we developed our work on TAAR5 applying a structure-based computational protocol, revolving around homology modeling and virtual screening calculations. In detail, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 model was employed to perform a virtual screening of an in-house library of compounds, including different five-membered ring derivatives, linked to a phenyl ring through a flexible or a rigid basic moiety. The computational protocol applied allowed to select a number of chemical scaffolds that were tested in a biological assay leading to the discovery of the first two mTAAR5 antagonists.
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- 2016
60. Exhaustive 3D-QSAR analyses as a computational tool to explore the potency and selectivity profiles of thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDE7 inhibitors
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Chiara Brullo, Olga Bruno, Elena Cichero, and Paola Fossa
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0301 basic medicine ,Quantitative structure–activity relationship ,Chemistry ,Ligand ,General Chemical Engineering ,Chemistry (all) ,Rational design ,Phosphodiesterase ,General Chemistry ,Combinatorial chemistry ,03 medical and health sciences ,030104 developmental biology ,PDE4B ,Docking (molecular) ,Potency ,Chemical Engineering (all) ,Pharmacophore - Abstract
The development of selective ligands binding to specific PDE isoforms represents an urgent need in medicinal chemistry, being a necessary strategy to identify many more drug-like compounds, to be investigated for several therapies. Concerning inflammation, rational design of selective PDE7 inhibitors over PDE4 could lead to derivatives endowed with a better safety profile, showing limited side-effects. In this context, thieno[3,2-d]pyrimidin-4(3H)-one-based compounds have been recently studied as a series of potent phosphodiesterase type 7 (PDE7) inhibitors, most of them being selective over other PDE enzymes, such as PDE4B. This work describes a computational study based on docking calculations followed by Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA), in order to better elucidate the pharmacophore features of this series of PDE7 inhibitors. The results reveal the ligand-based approach as a promising strategy to better investigate the potency and selectivity issues of PDE7 inhibitors. In addition, the results also allowed robust statistical models able to predict the potency and selectivity trend of new analogues prior to synthesis to be obtained.
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- 2016
61. Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT
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Silvia, Franchini, Leda Ivanova, Bencheva, Umberto Maria, Battisti, Annalisa, Tait, Claudia, Sorbi, Paola, Fossa, Elena, Cichero, Simone, Ronsisvalle, Giuseppina, Aricò, Nunzio, Denora, Rosa Maria, Iacobazzi, Antonio, Cilia, Lorenza, Pirona, and Livio, Brasili
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Structure-Activity Relationship ,Neuroprotective Agents ,Dose-Response Relationship, Drug ,Molecular Structure ,Central Nervous System Diseases ,Receptor, Serotonin, 5-HT1A ,Humans ,Neuralgia ,Dioxolanes ,Serotonin Receptor Agonists - Abstract
Targeting 5-HTA series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at αThe most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT
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- 2018
62. Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1receptor ligand antagonists
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Laura García-Toscano, Gérard Aimé Pinna, Giulio Ragusa, Paola Fossa, Battistina Asproni, María Gómez-Cañas, Elena Cichero, Giovanni Loriga, Valentina Satta, Francesco Deligia, Javier Fernández-Ruiz, Ruth Pazos, and Gabriele Murineddu
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0301 basic medicine ,CB1 antagonism ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Ligands ,01 natural sciences ,Sulfamerazine ,Biochemistry ,Rimonabant ,Drug Discovery ,Cannabinoid receptor type 2 ,Docking studies ,Receptor ,chemistry.chemical_classification ,Sulfonamides ,Molecular Structure ,ADMET model ,CB1antagonism ,Diarylpyridazines ,Sulfenamides ,Dose-Response Relationship, Drug ,Humans ,Molecular Docking Simulation ,Pyridazines ,Receptor, Cannabinoid, CB1 ,Structure-Activity Relationship ,Molecular Medicine ,Molecular Biology ,3003 ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Ligand (biochemistry) ,CB1 ,lipids (amino acids, peptides, and proteins) ,Drug ,medicine.drug ,Agonist ,Stereochemistry ,medicine.drug_class ,Dose-Response Relationship ,03 medical and health sciences ,medicine ,Inverse agonist ,Cannabinoid ,010405 organic chemistry ,0104 chemical sciences ,Sulfonamide ,030104 developmental biology ,chemistry - Abstract
A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.
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- 2018
63. Speeding up the identification of cystic fibrosis transmembrane conductance regulator-targeted drugs: An approach based on bioinformatics strategies and surface plasmon resonance
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Luis J. V. Galietta, Davide Sala, Pasqualina D'Ursi, Gabriele Trombetti, Luciano Milanesi, Enrico Millo, Elena Cichero, Paola Fossa, Margherita Di Somma, Alessandro Orro, Marco Rusnati, Chiara Urbinati, Antonella Bugatti, Rusnati, Marco, Sala, Davide, Orro, Alessandro, Bugatti, Antonella, Trombetti, Gabriele, Cichero, Elena, Urbinati, Chiara, Di Somma, Margherita, Millo, Enrico, Galietta, Luis J. V., Milanesi, Luciano, Fossa, Paola, and D’Ursi, Pasqualina
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0301 basic medicine ,Computational chemistry ,Molecular dynamic ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Cystic Fibrosis Transmembrane Conductance Regulator ,Bioinformatics ,01 natural sciences ,Cystic fibrosis ,Analytical Chemistry ,Ubiquitin ,Computational chemistry, Cystic fibrosis, Molecular dynamics, Molecular modeling, Surface plasmon resonance, Organic Chemistry ,Drug Discovery ,Surface plasmon resonance ,biology ,Chemistry ,respiratory system ,Cystic fibrosis transmembrane conductance regulator ,Chemistry (miscellaneous) ,Cystic fibrosi ,computational chemistry ,cystic fibrosis ,molecular dynamics ,molecular modeling ,surface plasmon resonance ,Molecular Medicine ,Human ,Protein Binding ,congenital, hereditary, and neonatal diseases and abnormalities ,In silico ,Molecular modeling ,Molecular dynamics ,Molecular Dynamics Simulation ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Humans ,Physical and Theoretical Chemistry ,ΔF508 ,Binding Sites ,010405 organic chemistry ,Endoplasmic reticulum ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Binding Site ,Computational Biology ,Surface Plasmon Resonance ,medicine.disease ,0104 chemical sciences ,respiratory tract diseases ,Thiazoles ,030104 developmental biology ,Chaperone (protein) ,biology.protein ,Thiazole - Abstract
Cystic fibrosis (CF) is mainly caused by the deletion of Phe 508 (DeltaF508) in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. New drugs able to rescue DeltaF508-CFTR trafficking are eagerly awaited. An integrated bioinformatics and surface plasmon resonance (SPR) approach was here applied to investigate the rescue mechanism(s) of a series of CFTR-ligands including VX809, VX770 and some aminoarylthiazole derivatives (AAT). Computational studies tentatively identified a large binding pocket in the DeltaF508-CFTR nucleotide binding domain-1 (NBD1) and predicted all the tested compounds to bind to three sub-regions of this main pocket. Noticeably, the known CFTR chaperone keratin-8 (K8) seems to interact with some residues located in one of these sub-pockets, potentially interfering with the binding of some ligands. SPR results corroborated all these computational findings. Moreover, for all the considered ligands, a statistically significant correlation was determined between their binding capability to DeltaF508-NBD1 measured by SPR and the pockets availability measured by computational studies. Taken together, these results demonstrate a strong agreement between the in silico prediction and the SPR-generated binding data, suggesting a path to speed up the identification of new drugs for the treatment of cystic fibrosis.
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- 2018
64. Fluorometric detection of protein-ligand engagement: The case of phosphodiesterase5
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Marco Sola, Giulia Di Rocco, Elena Cichero, Ilaria Martinelli, Paola Fossa, Glauco Ponterini, Silvia Franchini, Salvatore Pacifico, Mauro Giorgi, Remo Guerrini, and Silvia Cardarelli
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0301 basic medicine ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Pharmaceutical Science ,Plasma protein binding ,Ligands ,Analytical Chemistry ,Tadalafil ,0302 clinical medicine ,Catalytic Domain ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Cyclic GMP ,Spectroscopy ,chemistry.chemical_classification ,cGMPS-rhodamine ,Phosphodiesterase ,Recombinant Proteins ,Affinity constant (Kd) ,Isoenzymes ,Molecular Docking Simulation ,030220 oncology & carcinogenesis ,Competitive displacement analysis ,Fluorometric ligand binding detection ,Förster resonance energy transfer (FRET) ,Phosphodiesterase 5 ,3003 ,Drug Discovery3003 Pharmaceutical Science ,Protein Binding ,Stereochemistry ,NO ,03 medical and health sciences ,Humans ,Fluorescent Dyes ,Förster resonance energy transfer (FRET) ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Ligand ,Rhodamines ,Phosphodiesterase 5 Fluorometric ligand binding detection Competitive displacement analysis cGMPS-rhodamine Fo ̈rsterresonanceenergytransfer(FRET) Affinity constant (Kd) ,Phosphodiesterase 5 Inhibitors ,Affinities ,030104 developmental biology ,Enzyme ,Förster resonance energy transfer ,chemistry ,Models, Chemical ,Biophysics ,Conjugate ,Protein ligand - Abstract
Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities. The new approach takes advantage of Forster Resonance Energy Transfer (FRET) between, as the donor, a fluorescein-like diarsenical probe able to covalently bind a tetracysteine motif fused to the recombinant PDE5 catalytic domain and, as the acceptor, a rhodamine probe covalently bound to the pseudosubstrate cGMPS. The FRET efficiency decreases when a competitive ligand binds the PDE5 catalytic site and displaces the cGMPS-rhodamine conjugate. We have structurally investigated the PDE5/cGMPS-rhodamine complex by molecular modelling and have used the FRET signal to quantitatively characterize its binding equilibrium. Competitive displacement experiments were carried out with tadalafil and cGMPS. An adaptation of the competitive-displacement equilibrium model yielded the affinities for PDE5 of the incoming ligands, nano- and micromolar, respectively.
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- 2018
65. Rational design, chemical synthesis and biological evaluation of novel biguanides exploring species-specificity responsiveness of TAAR1 agonists
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Michele Tonelli, Raul R. Gainetdinov, Stefano Espinoza, Elena Cichero, Sara Guariento, and Andrey S. Gerasimov
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Bioluminescence Resonance Energy Transfer Techniques ,Models, Molecular ,0301 basic medicine ,Quantitative structure–activity relationship ,TAAR1 ,Biguanides ,Druggability ,Quantitative Structure-Activity Relationship ,Computational biology ,Chemical synthesis ,Receptors, G-Protein-Coupled ,Docking ,03 medical and health sciences ,Drug Discovery ,Humans ,Agonism ,TAAR1, Thyronamines, Agonists, QSAR, Docking, Biguanide ,G protein-coupled receptor ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Drug discovery ,QSAR ,Organic Chemistry ,Rational design ,Thyronamines ,General Medicine ,HEK293 Cells ,030104 developmental biology ,Docking (molecular) ,Drug Design ,Biguanide ,Agonists - Abstract
The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues.
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- 2018
66. Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools
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Annalisa Salis, Maria Arkel, Nara Liessi, Paola Fossa, Enrico Millo, Elena Cichero, Bruno Tasso, Emanuela Pesce, Gianluca Damonte, Luis J. V. Galietta, Valeria Tomati, Matteo Paccagnella, Nicoletta Pedemonte, Liessi, Nara, Cichero, Elena, Pesce, Emanuela, Arkel, Maria, Salis, Annalisa, Tomati, Valeria, Paccagnella, Matteo, Damonte, Gianluca, Tasso, Bruno, Galietta, Luis J. V., Pedemonte, Nicoletta, Fossa, Paola, and Millo, Enrico
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0301 basic medicine ,Quantitative structure–activity relationship ,VX809 ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quantitative Structure-Activity Relationship ,Gating ,Computational biology ,medicine.disease_cause ,01 natural sciences ,Cystic fibrosis ,Cell Line ,Corrector ,03 medical and health sciences ,chemistry.chemical_compound ,Mutant protein ,Drug Discovery ,medicine ,Humans ,Benzodioxoles ,CFTR ,Thiazole ,Aminoarylthiazole, CFTR, Corrector, Cystic fibrosis, QSAR, VX809 ,Biological evaluation ,Pharmacology ,Mutation ,Aminoarylthiazole ,010405 organic chemistry ,QSAR ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,General Medicine ,0104 chemical sciences ,Thiazoles ,Aminopyridine ,030104 developmental biology ,chemistry ,Cystic fibrosi ,Benzodioxole ,Human - Abstract
The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
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- 2018
67. Novel pyrrolocycloalkylpyrazole analogues as CB1 ligands
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Elena Cichero, G. A. Pinna, Giovanni Loriga, Paola Fossa, Battistina Asproni, Ilaria Manca, Gérard Aimé Pinna, Paolo Lazzari, and Gabriele Murineddu
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0301 basic medicine ,Cannabinoid receptor ,Stereochemistry ,medicine.medical_treatment ,Pyrazole ,Biochemistry ,pyrrolocycloalkylpyrazole ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,cannabinoid receptors ,binding affinity ,docking studies ,Molecular Medicine ,Drug Discovery ,Cannabinoid receptor type 2 ,medicine ,Pharmacology ,chemistry.chemical_classification ,Organic Chemistry ,030104 developmental biology ,chemistry ,Docking (molecular) ,Indolizine ,Cannabinoid ,030217 neurology & neurosurgery ,Tricyclic - Abstract
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nM, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nM. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (KiCB1 = 81 nM) and the highest CB2/CB1 selectively ratio (>12). Docking studies carried out on such compounds were performed by using the hCB1 X-ray in complex with the close pyrazole analogue AM6538, and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB1 ligands. This article is protected by copyright. All rights reserved.
- Published
- 2018
68. New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies
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Olga Bruno, Sara Guariento, Elena Cichero, and Paola Fossa
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Models, Molecular ,0301 basic medicine ,Gene isoform ,Subfamily ,Quantitative Structure-Activity Relationship ,Context (language use) ,Computational biology ,Pharmacology ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,PDE4B ,Drug Discovery ,Humans ,Protein Isoforms ,Physical and Theoretical Chemistry ,PDE4 Inhibitors ,Molecular Biology ,Chemistry ,Phosphodiesterases · PDE4B inhibitors · PDE4D · Molecular docking · Selectivity · CoMFA ,Organic Chemistry ,Rational design ,Computational Biology ,General Medicine ,Ligand (biochemistry) ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Molecular Docking Simulation ,030104 developmental biology ,Phosphodiesterase 4 Inhibitors ,Selectivity ,Protein Binding ,Information Systems - Abstract
PDE4 inhibitors have been largely studied because of their promising therapeutic effects concerning inflammation and neurodegenerative dysfunctions, such as depression, schizophrenia and Alzheimer's diseases. In this context, the PDE4B isoform proved to be particularly involved in the activation of inflammatory responses, while the PDE4D subfamily is more associated with neuropathologies. The clinical use of PDE4 inhibitors was restricted by the presence of prominent side effects probably due to their non-specific action across the different isoforms. Therefore, this work deals with the development of 3D-QSAR models, supported by molecular docking studies, to identify the key requirements underlying selective PDE4B or PDE4D inhibition. The results highlighted the ligand-based approach as a promising tool to guide the rational design of novel PDE4 inhibitors endowed with high affinity and selectivity profiles. The alignment of compound 1-85 and the model A statistical results are depicted.
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- 2015
69. Ligand-based homology modelling of the human CB2 receptor SR144528 antagonist binding site: a computational approach to explore the 1,5-diaryl pyrazole scaffold
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Paola Fossa, Sara Guariento, Elena Cichero, and Giulia Menozzi
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Pharmacology ,Stereochemistry ,Organic Chemistry ,Antagonist ,Pharmaceutical Science ,Computational biology ,Biology ,Biochemistry ,Drug Discovery ,Cannabinoid receptor type 2 ,Molecular Medicine ,Inverse agonist ,lipids (amino acids, peptides, and proteins) ,Homology modeling ,Binding site ,Signal transduction ,Receptor ,G protein-coupled receptor - Abstract
CB1 and CB2 receptors belong to the large family of G-protein coupled receptors (GPCRs), being involved in a wide variety of signal transduction processes. In this context, CB2 selective compounds were described in the literature to be active in different neuropathic and inflammatory pain models, also showing beneficial effects as neuroprotective agents. Indeed, CB2 proved to be up-regulated in reactive microglial cells in Alzheimer's disease (AD) and Huntington's, suggesting a promising therapeutic panorama for CB2 inverse agonists/antagonists. At present, the development of new selective CB2 antagonists is prevented by an unclear depiction of the reference antagonist SR144528 binding mode. Indeed, a few number of models concerning the CB2 receptor antagonist binding site have been proposed, leading sometimes to contradictory results. In this context, a specific hCB2 ligand-based homology model in the presence of the antagonist SR144528 was built. Notably, the refined model also allowed us to explore the pyrazole scaffold as prototype for CB2 ligand recognition and also to elucidate the CB1/CB2 structure–activity relationship of an in-house series of analogues we previously published. The derived information is expected to be a useful tool for guiding a much more focused and reliable CB2 antagonist design.
- Published
- 2015
70. Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB
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Gabriele, Murineddu, Francesco, Deligia, Giulio, Ragusa, Laura, García-Toscano, María, Gómez-Cañas, Battistina, Asproni, Valentina, Satta, Elena, Cichero, Ruth, Pazos, Paola, Fossa, Giovanni, Loriga, Javier, Fernández-Ruiz, and Gerard A, Pinna
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Molecular Docking Simulation ,Pyridazines ,Structure-Activity Relationship ,Sulfonamides ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor, Cannabinoid, CB1 ,Humans ,Ligands ,Sulfamerazine - Abstract
A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB
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- 2017
71. Structure-Activity Relationships within a Series of σ
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Silvia, Franchini, Claudia, Sorbi, Umberto Maria, Battisti, Annalisa, Tait, Leda Ivanova, Bencheva, Elena, Cichero, Paola, Fossa, Antonio, Cilia, Orazio, Prezzavento, Simone, Ronsisvalle, Giuseppina, Aricò, Luisa, Benassi, Cristina, Vaschieri, Paola, Azzoni, Cristina, Magnoni, and Livio, Brasili
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Male ,Models, Molecular ,Cell Death ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell Survival ,Antineoplastic Agents ,Crystallography, X-Ray ,Ligands ,Analgesics, Opioid ,Mice ,Structure-Activity Relationship ,Piperidines ,Animals ,Humans ,Receptors, sigma ,Spiro Compounds ,Drug Screening Assays, Antitumor ,Melanoma ,Cells, Cultured ,Cell Proliferation - Abstract
A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ
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- 2017
72. Novel pyrrolocycloalkylpyrazole analogues as CB
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Battistina, Asproni, Ilaria, Manca, Giansalvo, Pinna, Elena, Cichero, Paola, Fossa, Gabriele, Murineddu, Paolo, Lazzari, Giovanni, Loriga, and Gérard A, Pinna
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Molecular Docking Simulation ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,Binding Sites ,Receptor, Cannabinoid, CB1 ,Morpholines ,Humans ,Pyrazoles ,Azepines ,Ligands ,Half-Life ,Protein Binding ,Protein Structure, Tertiary - Abstract
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide-based compounds were designed and synthesized for cannabinoid CB
- Published
- 2017
73. Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists
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Livio Brasili, Giuseppina Aricò, Rosa Maria Iacobazzi, Claudia Sorbi, Lorenza Pirona, Leda Ivanova Manasieva, Silvia Franchini, Umberto Maria Battisti, Nunzio Denora, Antonio Cilia, Paola Fossa, Elena Cichero, and Simone Ronsisvalle
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Male ,0301 basic medicine ,Agonist ,Analgesic activity ,Serotonin ,Molecular model ,medicine.drug_class ,Stereochemistry ,Pain ,Partial agonist ,5-HT1A receptor ,BBB penetration ,Neuroprotection ,Pharmacology ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Models ,Formaldehyde ,Alkanes ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Spiro Compounds ,Analgesics ,Blood-Brain Barrier ,Models, Molecular ,Pain Measurement ,Receptor, Serotonin, 5-HT1A ,Serotonin 5-HT1 Receptor Agonists ,ADME ,Molecular ,General Medicine ,Piperazine ,030104 developmental biology ,chemistry ,5-HT1A ,Amine gas treating ,Selectivity ,030217 neurology & neurosurgery ,Receptor - Abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.
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- 2017
74. Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus
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Maria Paola Costi, Anna Moroni, Roberta Loddo, Matteo Santucci, Elena Cichero, Bruno Tasso, Sabrina Gazzarrini, Michele Tonelli, and Lieve Naesens
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Models, Molecular ,0301 basic medicine ,viruses ,Crystallography, X-Ray ,01 natural sciences ,2-dihydrotriazine derivatives ,chemistry.chemical_compound ,Influenza A Virus, H1N1 Subtype ,Models ,Drug Discovery ,Dihydrofolate reductase ,6-diamino-1 ,1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives ,Influenza A Virus ,1-Aryl-4 ,Crystallography ,biology ,Molecular Structure ,Triazines ,General Medicine ,Resistance mutation ,Host (human) DHFR inhibition ,Respiratory Syncytial Viruses ,Proguanil ,Anti-influenza A and B viruses activity ,Anti-RSV activity ,Antiviral Agents ,Dose-Response Relationship, Drug ,Folic Acid Antagonists ,Humans ,Influenza B virus ,Microbial Sensitivity Tests ,Structure-Activity Relationship ,Tetrahydrofolate Dehydrogenase ,Pharmacology ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives, Anti-influenza A and B viruses activity, Anti-RSV activity, Host (human) DHFR inhibition ,Drug ,medicine.drug ,Cycloguanil ,Article ,Virus ,Dose-Response Relationship ,03 medical and health sciences ,Zanamivir ,medicine ,H1N1 Subtype ,Ribavirin ,Molecular ,Virology ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,chemistry ,M2 proton channel ,biology.protein ,X-Ray - Abstract
We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC50 = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC50 = 5.8 μM, SI > 43)., Graphical abstract Image 1, Highlights • 4,6-Diamino-1,2-dihydrotriazines were found active against influenza A and B viruses. • 4,6-Diamino-1,2-dihydrotriazines displayed high antiviral activity against RSV virus. • Their mechanism of action was related to the inhibition of the host (human) DHFR.
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- 2017
75. Benzimidazole-based derivatives as privileged scaffold developed for the treatment of the RSV infection: a computational study exploring the potency and cytotoxicity profiles
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Olga Bruno, Elena Cichero, Federica Novelli, Bruno Tasso, Roberta Loddo, Paola Fossa, Michele Tonelli, and Ilenia Delogu
- Subjects
Models, Molecular ,0301 basic medicine ,Palivizumab ,Benzimidazole ,Scaffold ,Quantitative structure–activity relationship ,CoMFA ,Stereochemistry ,respiratory syncytial virus ,Quantitative Structure-Activity Relationship ,Microbial Sensitivity Tests ,Computational biology ,Biology ,010402 general chemistry ,Antiviral Agents ,Respirovirus Infections ,01 natural sciences ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Cytotoxicity ,Vero Cells ,3D-QSAR ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,lcsh:RM1-950 ,General Medicine ,Respiratory Syncytial Viruses ,0104 chemical sciences ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,chemistry ,Original Article ,Benzimidazoles ,medicine.drug ,CoMSIA - Abstract
Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents.
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- 2017
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76. New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking
- Author
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Nadine Jagerovic, Gérard Aimé Pinna, María Ruth Pazos, María Gómez-Cañas, Gabriele Murineddu, Carmen Rodríguez-Cueto, Giulio Ragusa, Paola Fossa, Battistina Asproni, Elena Cichero, Javier Fernández-Ruiz, Paula Morales, Ministerio de Economía, Industria y Competitividad (España), and Comunidad de Madrid
- Subjects
0301 basic medicine ,Cannabinoid receptor ,Drug Inverse Agonism ,Stereochemistry ,Protein Conformation ,medicine.medical_treatment ,Chemistry Techniques, Synthetic ,01 natural sciences ,Receptor, Cannabinoid, CB2 ,03 medical and health sciences ,Synthesis ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Cannabinoid receptor type 2 ,Inverse agonist ,Humans ,Docking studies ,Receptor ,Cannabinoid receptors ,ADME ,Pharmacology ,Cannabinoid Receptor Agonists ,Scaffold hopping ,010405 organic chemistry ,Chemistry ,Ligand binding assay ,Organic Chemistry ,General Medicine ,ADME model ,CB2 antagonism ,Combinatorial chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,Pyridazines ,030104 developmental biology ,HEK293 Cells ,Docking (molecular) ,Guanosine 5'-O-(3-Thiotriphosphate) ,Cannabinoid - Abstract
In the last few years, cannabinoid type-2 receptor (CBR) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCBR and hCBR. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB-affinity (KCB = 2.0 ± 0.81 nM) and a notable selectivity (KCB/KCB > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CBR inverse agonists in [S]-GTPγS binding assay. ADME predictions of the newly synthesized CBR ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CBR ligands., JFR and NJ thanks the MINECO (Plan Nacional de Biomedicina) for the joint grant SAF2015-68580-C2 (1-R to JFR and 2-R to NJ) and the “Programa de Biomedicina, Comunidad de Madrid” for the grant S2011/BMD-2308
- Published
- 2016
77. Homology Modeling, Docking Studies and Molecular Dynamic Simulations Using Graphical Processing Unit Architecture to Probe the Type-11 Phosphodiesterase Catalytic Site: A Computational Approach for the Rational Design of Selective Inhibitors
- Author
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Pasqualina D'Ursi, Alessandro Orro, Luciano Milanesi, Marco Moscatelli, Chiara Rotolo, Paola Fossa, Elena Cichero, and Olga Bruno
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Phosphodiesterase Inhibitors ,homology modeling ,In silico ,Molecular Sequence Data ,Pyrimidinones ,Computational biology ,Molecular Dynamics Simulation ,Biology ,Crystallography, X-Ray ,Biochemistry ,chemistry.chemical_compound ,3',5'-Cyclic-GMP Phosphodiesterases ,Graphical Processing Unit computing ,Catalytic Domain ,Drug Discovery ,Humans ,Cyclic adenosine monophosphate ,Amino Acid Sequence ,Homology modeling ,Cyclic guanosine monophosphate ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Pharmacology ,Binding Sites ,Phosphoric Diester Hydrolases ,3D-model ,Organic Chemistry ,selectivity ,Rational design ,Phosphodiesterase ,molecular docking ,catalytic site ,molecular dynamic simulations ,Molecular Docking Simulation ,chemistry ,Docking (molecular) ,Drug Design ,phosphodiesterase 11 ,Molecular Medicine ,Zaprinast ,Sequence Alignment ,Protein Binding - Abstract
Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors.
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- 2013
78. Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2- a ]benzimidazol-4(10 H )-ones
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Giuliana Leoncini, Silvana Alfei, Giancarlo Grossi, Maria Grazia Signorello, Paola Fossa, Gianluca Damonte, Elena Cichero, and Mario Di Braccio
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Blood Platelets ,Models, Molecular ,Pharmacology ,Gene isoform ,Dose-Response Relationship, Drug ,Molecular Structure ,Platelet aggregation ,Chemistry ,Stereochemistry ,In silico ,Organic Chemistry ,Phosphodiesterase 3 ,Ionophore ,Human platelet ,Pyrimidinones ,General Medicine ,Crystallography, X-Ray ,In vitro ,Structure-Activity Relationship ,Reference Values ,Drug Discovery ,Humans ,Benzimidazoles ,Platelet Aggregation Inhibitors - Abstract
The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2- a ]benzimidazol-4(10 H )-ones 6a – o , and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2- a ]benzimidazol-4(10 H )-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2- a ]benzimidazol-2(10 H )-one 13 , as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca 2+ ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives ( 6g – o ) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series ( 6i and 6o ) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor.
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- 2013
79. Insights into the Structure and Pharmacology of the Human Trace Amine-Associated Receptor 1 (hTAAR1): Homology Modelling and Docking Studies
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Paola Fossa, Elena Cichero, Stefano Espinoza, Livio Brasili, and Raul R. Gainetdinov
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Pharmacology ,Organic Chemistry ,RO5166017 ,Biology ,Biochemistry ,Molecular Docking Simulation ,Docking (molecular) ,TAAR1 ,Drug Discovery ,Molecular Medicine ,Homology modeling ,Receptor ,Trace amine-associated receptor ,G protein-coupled receptor - Abstract
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.
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- 2013
80. Novel biguanide-based derivatives scouted as TAAR1 agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies
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Stefano Espinoza, Elena Cichero, Michele Tonelli, and Raul R. Gainetdinov
- Subjects
0301 basic medicine ,medicine.drug_class ,Protein Conformation ,Biguanides ,Endogeny ,Chemistry Techniques, Synthetic ,Neurotransmission ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,TAAR5 ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,TAAR1 ,Drug Discovery ,medicine ,Animals ,Humans ,Computer Simulation ,Receptor ,ADME ,Pharmacology ,Biguanide ,Chemistry ,Ligand ,Organic Chemistry ,General Medicine ,Molecular Docking Simulation ,030104 developmental biology ,Biochemistry ,Absorption, Physicochemical ,Drug Design ,030217 neurology & neurosurgery - Abstract
Trace amines (TAs) are endogenous neuromodulators that play a functional role in the synaptic transmission within central nervous system (CNS), targeting trace amine-associated receptors (TAARs). Starting from our previous computational studies on TAAR1 and TAAR5 interactions with the unselective ligand 3-iodothyronamine (T1AM), we investigated the functional activity at murine and human TAAR1 and murine TAAR5 receptors of twenty-seven biguanide-based derivatives, including six newly synthesized compounds. Phenyl (BIG2, BIG4, BIG8 and BIG22) or benzyl (BIG10-BIG16) biguanides were found to be selective murine and human TAAR1 agonists with potencies in nanomolar or low micromolar range, respectively. In particular, compounds BIG2 and BIG12-BIG14 were the most promising and they could be considered valuable lead compounds worthy of further investigations. In addition to the interest for developing more effective human TAAR1 ligands, the disclosed here potent murine TAAR1 agonists could offer suitable tools for studying the pharmacology of TAAR1 receptor.
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- 2016
81. New insights into the structure of the trace amine-associated receptor 2: Homology modelling studies exploring the binding mode of 3-iodothyronamine
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Elena Cichero and Michele Tonelli
- Subjects
0301 basic medicine ,In silico ,Molecular Sequence Data ,Computational biology ,Ligands ,Biochemistry ,Receptors, G-Protein-Coupled ,3-Iodothyronamine ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,TAAR2 ,TAAR1 ,Drug Discovery ,Leukocytes ,Thyronines ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Trace amine-associated receptor ,G protein-coupled receptor ,Pharmacology ,Binding Sites ,Organic Chemistry ,Protein Structure, Tertiary ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Docking (molecular) ,Molecular Medicine ,Sequence Alignment ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Recent studies have further investigated the trace amine-associated receptor type 2 (TAAR2) pharmacology, revealing its role not only at the olfactory sensory neurons but also at the immune system, being expressed in human leucocytes. In particular, the ability of this receptor to bind the unselective TAAR ligand 3-iodo-thyronamine (T1 AM) was elucidated, making in the meanwhile the discovery of selective compounds a urgent need to derive much more suitable tools for studying TAARs. In this context, we developed our work on TAAR2 applying a structure-based computational protocol, including TAAR2 homology modelling and T1 AM docking studies. The results were compared with those we previously obtained about TAAR1, in order to point out new insights guiding for selectivity between TAAR1 and TAAR2. The in silico strategy applied allowed us to provide for the first time thorough TAAR2 homology models, which are expected to be useful tools for a further design process of more selective TAAR ligands.
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- 2016
82. Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT
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Silvia, Franchini, Leda Ivanova, Manasieva, Claudia, Sorbi, Umberto M, Battisti, Paola, Fossa, Elena, Cichero, Nunzio, Denora, Rosa Maria, Iacobazzi, Antonio, Cilia, Lorenza, Pirona, Simone, Ronsisvalle, Giuseppina, Aricò, and Livio, Brasili
- Subjects
Male ,Models, Molecular ,Analgesics ,Pain ,Serotonin 5-HT1 Receptor Agonists ,Mice ,Structure-Activity Relationship ,Blood-Brain Barrier ,Formaldehyde ,Alkanes ,Receptor, Serotonin, 5-HT1A ,Animals ,Humans ,Spiro Compounds ,Pain Measurement - Abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT
- Published
- 2016
83. Synthesis, molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB
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Antonio, Dore, Battistina, Asproni, Alessia, Scampuddu, Stefania, Gessi, Gabriele, Murineddu, Elena, Cichero, Paola, Fossa, Stefania, Merighi, Serena, Bencivenni, and Gérard A, Pinna
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Models, Molecular ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor, Cannabinoid, CB1 ,Humans ,Naphthyridines - Abstract
Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB
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- 2016
84. Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics
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Luciano Milanesi, Sara Guariento, Elena Cichero, Paola Fossa, Olga Bruno, Alessandro Orro, Gabriele Trombetti, and Pasqualina D'Ursi
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0301 basic medicine ,Stereochemistry ,Computational biology ,Biology ,Molecular Dynamics Simulation ,03 medical and health sciences ,Molecular dynamics ,Docking ,PDE4 ,PDE4D selective inhibitors ,Phosphodiesterases ,Molecular Medicine ,Structural Biology ,Organic Chemistry ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,Drug Discovery3003 Pharmaceutical Science ,Drug Discovery ,Humans ,Protein Isoforms ,Enzyme Inhibitors ,chemistry.chemical_classification ,Binding Sites ,Full Paper ,Rational design ,Full Papers ,molecular dynamics ,3. Good health ,Computer Science Applications ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Molecular Docking Simulation ,030104 developmental biology ,Enzyme ,chemistry ,Docking (molecular) ,docking ,Protein Binding - Abstract
Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D‐MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in‐house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors.
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- 2016
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85. Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study
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Martina Sabatini, Laura Raimondi, Riccardo Zucchi, Stefano Espinoza, Simona Rapposelli, Annunziatina Laurino, Giulia Nesi, Lorenza Bellusci, Elena Cichero, Sara Chiarugi, Simona Sestito, Raul R. Gainetdinov, Massimiliano Runfola, Grazia Chiellini, and Paola Fossa
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0301 basic medicine ,Agonist ,medicine.drug_class ,Stereochemistry ,thyronamines ,TAAR1 ,Diphenylmethane ,trace amines ,Receptors, G-Protein-Coupled ,diphenylmethane-scaffold ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,mTAAR1 agonist ,Thyronamine ,T1AM ,T0AM ,Benzhydryl Compounds ,Receptor ,Cells, Cultured ,G protein-coupled receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Hep G2 Cells ,Hit to lead ,Molecular Docking Simulation ,HEK293 Cells ,030104 developmental biology ,chemistry ,Drug Design ,030220 oncology & carcinogenesis ,Molecular Medicine ,Lead compound - Abstract
The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1-16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models.
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- 2016
86. Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives
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Giuseppina Aricò, Livio Brasili, Adolfo Prandi, Annalisa Tait, Antonio Cilia, Paola Fossa, Orazio Prezzavento, Umberto Maria Battisti, Silvia Franchini, Simone Ronsisvalle, Carmela Parenti, Elena Cichero, and Chiara Borsari
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0301 basic medicine ,Models, Molecular ,Sigma receptors ligands ,Sigma-1 ,Piperidine Piperazine 1,3-Dioxolane ,Receptor-mediated analgesia ,Sigma-2 ,Molecular model ,Receptors, Opioid, mu ,sigma ,Ligands ,chemistry.chemical_compound ,Models ,3-Dioxolane ,Receptors ,Drug Discovery ,1,3-Dioxolane ,Piperazine ,Piperidine ,Analgesics, Opioid ,Animals ,Brain ,Dioxolanes ,Guinea Pigs ,Humans ,Molecular Docking Simulation ,Morphine ,Pain ,Rats ,Receptors, Opioid, kappa ,Receptors, sigma ,Structure-Activity Relationship ,Pharmacology ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Analgesics ,Biological activity ,General Medicine ,Dioxolane ,Agonist ,medicine.drug_class ,Stereochemistry ,Sigma receptor ,Opioid ,03 medical and health sciences ,medicine ,Structure–activity relationship ,Homology modeling ,kappa ,Piperidine Piperazine 1 ,Molecular ,030104 developmental biology ,chemistry ,mu ,Docking (molecular) - Abstract
Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
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- 2016
87. Synthesis, molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB2receptor antagonists/inverse agonists
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Serena Bencivenni, Antonio Dore, Stefania Merighi, Gérard Aimé Pinna, Alessia Scampuddu, Stefania Gessi, Paola Fossa, Battistina Asproni, Elena Cichero, and Gabriele Murineddu
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0301 basic medicine ,Molecular model ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,Carboxamide ,Hydrazide ,Cannabinoid receptors, CB2antagonism/inverse agonism, Docking studies, Pyrazolo[5,1-f][1,6]naphthyridine, Biochemistry, Molecular Medicine, Molecular Biology, 3003, Drug Discovery, 3003 Pharmaceutical Science, Clinical Biochemistry, Organic Chemistry ,1-f][1 ,Biochemistry ,NO ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pyrazolo[5 ,Drug Discovery ,medicine ,Inverse agonist ,Moiety ,Docking studies ,Cannabinoid receptors ,Molecular Biology ,CB2antagonism/inverse agonism ,antagonism/inverse agonism ,6]naphthyridine ,CB ,2 ,Pyrazolo[5,1-f][1,6]naphthyridine ,Organic Chemistry ,Antagonist ,030104 developmental biology ,chemistry ,Docking (molecular) ,Molecular Medicine ,Selectivity ,030217 neurology & neurosurgery - Abstract
Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB1 and CB2 receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a–i) or a 2,4-dichlorophenyl (8j) motif at the C5-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C2-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB2 receptor affinity (Ki = 33 nM) and a high degree of selectivity (KiCB1/KiCB2 = 173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, Ki = 53 nM) and the myrtanyl derivative 8j (Ki = 67 nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB2 inverse agonists.
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- 2016
88. CoMFA and CoMSIA analyses on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine derivatives as selective CB2 receptor agonists
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Sara Cesarini, Paola Fossa, Luisa Mosti, and Elena Cichero
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Models, Molecular ,Quantitative structure–activity relationship ,CoMFA ,Stereochemistry ,Quantitative Structure-Activity Relationship ,Cb2 agonist ,4-dihydro-1 ,Catalysis ,Receptor, Cannabinoid, CB2 ,Inorganic Chemistry ,Cannabinoid receptor type 2 ,Humans ,Naphthyridines ,Physical and Theoretical Chemistry ,5 ,Chemistry ,CoMSIA ,4-oxo-1 ,4-dihydroquinoline derivatives ,1 ,6- and -1 ,8-naphthyridine derivatives ,CB2 receptor agonists ,Organic Chemistry ,Order (ring theory) ,Computer Science Applications ,Computational Theory and Mathematics ,Quinolines ,Selectivity ,Protein Binding - Abstract
Novel classes of CB2 agonists based on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over CB1. A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing \( r_{ncv}^2 = 0.84 \), \( r_{cv}^2 = ~0.619 \), SEE = 0.369, and \( r_{pred}^2 = 0.75 \). The study provides useful suggestions for the synthesis of new selective analogues with improved affinity.
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- 2009
89. Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists
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Laura Raimondi, Annunziatina Laurino, Rossella Malvasi, Paola Fossa, Riccardo Zucchi, Elena Cichero, Maria Digiacomo, Stefano Espinoza, Marco Macchia, Martina Sabatini, Simona Rapposelli, Grazia Chiellini, Raul R. Gainetdinov, Sabina Frascarelli, and Giulia Nesi
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Blood Glucose ,Male ,Models, Molecular ,Thyronamine ,Stereochemistry ,thyronamines ,Molecular Sequence Data ,Wistar ,Endogeny ,Ligands ,Receptors, G-Protein-Coupled ,Small Molecule Libraries ,G-Protein-Coupled ,chemistry.chemical_compound ,Mice ,Models ,In vivo ,TAAR1 ,Receptors ,Drug Discovery ,Thyronines ,Animals ,Humans ,Amino Acid Sequence ,Rats, Wistar ,Drug Design ,HEK293 Cells ,Molecular Medicine ,Drug Discovery3003 Pharmaceutical Science ,Medicine (all) ,Receptor ,G protein-coupled receptor ,Chemistry ,HEK 293 cells ,Molecular ,trace amine associated receptors ,In vitro ,Rats ,Biochemistry - Abstract
Trace amine associated receptor 1 (TAAR1) is a G protein coupled receptor (GPCR) expressed in brain and periphery activated by a wide spectrum of agonists that include, but are not limited to, trace amines (TAs), amphetamine-like psychostimulants, and endogenous thyronamines such as thyronamine (T0AM) and 3-iodothyronamine (T1AM). Such polypharmacology has made it challenging to understand the role and the biology of TAAR1. In an effort to understand the molecular basis of TAAR1 activation, we rationally designed and synthesized a small family of thyronamine derivatives. Among them, compounds 2 and 3 appeared to be a good mimic of the parent endogenous thyronamine, T0AM and T1AM, respectively, both in vitro and in vivo. Thus, these compounds offer suitable tools for studying the physiological roles of mouse TAAR1 and could represent the starting point for the development of more potent and selective TAAR1 ligands.
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- 2015
90. Fight Against H1N1 Influenza A Virus: Recent Insights Towards the Development of Druggable Compounds
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Michele Tonelli and Elena Cichero
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0301 basic medicine ,Pharmacology ,biology ,Organic Chemistry ,H1N1 influenza ,Druggability ,Hemagglutinin (influenza) ,Influenza a ,Computational biology ,medicine.disease_cause ,Biochemistry ,Virology ,Antiviral Agents ,Virus ,03 medical and health sciences ,030104 developmental biology ,Influenza A Virus, H1N1 Subtype ,Drug Design ,Drug Discovery ,biology.protein ,Influenza A virus ,medicine ,Molecular Medicine ,Humans ,Neuraminidase - Abstract
In this review we discuss drug design strategies directed to the development of potential anti-influenza A(H1N1) inhibitors of M2 ion channel, neuraminidase (NA), hemagglutinin (HA) and RNA-dependent RNA-polymerase complex (RdRp) major targets, following temporal chronology of their findings. Besides searching for new chemotypes, eventually active against new targets of influenza A (H1N1), the design of optimized analogues of proven drugs is largely pursued, taking into account the emerging insight into the mechanisms of resistance to existing antivirals. Computational studies are also summarized, in order to highlight the structural requirements for further chemical optimizations.
- Published
- 2015
91. In silico evaluation of human small heat shock protein HSP27: homology modeling, mutation analyses and docking studies
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Paola Fossa and Elena Cichero
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Protein Folding ,animal structures ,In silico ,Clinical Biochemistry ,Mutant ,Static Electricity ,Cancer therapy ,HSP27 Heat-Shock Proteins ,Pharmaceutical Science ,Gene Expression ,Antineoplastic Agents ,Computational biology ,Molecular Dynamics Simulation ,Biochemistry ,Small Molecule Libraries ,Structure-Activity Relationship ,Hsp27 ,Heat shock protein ,Drug Discovery ,Humans ,Homology modeling ,Molecular Biology ,Heat-Shock Proteins ,Genetics ,biology ,Organic Chemistry ,Hydrogen Bonding ,Molecular Docking Simulation ,Docking (molecular) ,Structural Homology, Protein ,Mutation ,biology.protein ,Molecular Medicine ,Protein folding ,Molecular Chaperones ,Protein Binding - Abstract
Small heat-shock proteins, possessing chaperone-like activity, represented crucial proteins actively involved in maintain protein homeostasis, which act to prevent improper polypeptide aggregation and deposition of misfolded proteins. In this context, a number of mutations concerning the HspB1 protein proved to be associated with the development of several neuropathologies. Unfortunately, molecular mechanisms underlying the onset of these diseases and in particular the changes induced by the mutations in HspB1 structure, remain poorly characterized. On the other hand, more recent studies demonstrated that HspB1 overexpression leads to an overactive chaperone activity, which in turn contributes to the anticancer agent resistance. On these basis, Hsp27 could represent a good innovative target for development of novel cancer therapy. Therefore, in this work a computational study, based on the homology model of the complete Hsp27 protein and of several pathological mutant forms, was developed. Finally, the derived model was employed to perform, for the first time, docking simulations on a recently identified Hsp27 inhibitor, disclosing a new useful panorama to be exploited for the further development of new compounds.
- Published
- 2015
92. Enantiomeric resolution of [(2,2-diphenyl-1,3-dioxolan-4-yl)methyl](2-phenoxyethyl)amine, a potent α1 and 5-HT1A receptor ligand: an in vitro and computational study
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Piero Angeli, Anna Maria Baraldi, Claudia Sorbi, Federica Pellati, Antonio Cilia, Umberto Maria Battisti, Livio Brasili, Elena Cichero, and Silvia Franchini
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Agonist ,alpha1 adrenoceptor ,medicine.drug_class ,Stereochemistry ,3-dioxolane ,Pharmaceutical Science ,ligand ,Biochemistry ,Enantioseparation ,Drug Discovery ,polycyclic compounds ,medicine ,heterocyclic compounds ,5-HT1A receptor ,stereoselective synthesis ,Pharmacology ,Enantioseparation, stereoselective synthesis, 1,3-dioxolane, alpha1 adrenoceptor, 5-HT1A receptor, ligand ,Ligand ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Absolute configuration ,In vitro ,Molecular Medicine ,Stereoselectivity ,Amine gas treating ,Enantiomer - Abstract
In this paper, the enantiomers of (±)-1, previously studied as α1 and 5-HT1A ligands, were prepared both by resolution of the racemate and asymmetric synthesis. The enantiomeric purity and absolute configuration were determined by means of HPLC and polarimetric analysis. Enantiomers were evaluated for in vitro 5-HT1A and α1 receptor affinity by binding and functional assays. Results indicate that the two enantiomers are almost equally potent at 5-HT1A and α1 receptor systems and, contrary to WB 4101, the stereoselectivity is poor. As further support to these experimental findings, molecular docking studies on the two enantiomers of (±)-1 have been performed and a comparison with those obtained for 5-HT1A potent agonist (R)-flesinoxan and α1d antagonist (S)-WB 4101 has been drawn.
- Published
- 2015
93. Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis
- Author
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Annalisa Salis, Andrea Galatini, Enrico Millo, Nicoletta Pedemonte, Sara Guariento, Elena Cichero, Paola Fossa, Ambra Gianotti, Nara Liessi, Emanuela Pesce, Gianluca Damonte, Marta Bellotti, Olga Zegarra-Moran, Luis J. V. Galietta, Pesce, Emanuela, Bellotti, Marta, Liessi, Nara, Guariento, Sara, Damonte, Gianluca, Cichero, Elena, Galatini, Andrea, Salis, Annalisa, Gianotti, Ambra, Pedemonte, Nicoletta, Zegarra-Moran, Olga, Fossa, Paola, Galietta, Luis J. V., and Millo, Enrico
- Subjects
Models, Molecular ,congenital, hereditary, and neonatal diseases and abnormalities ,Stereochemistry ,Cystic Fibrosis Transmembrane Conductance Regulator ,Gating ,Chemistry Techniques, Synthetic ,Chloride ,Cystic fibrosis ,Cell Line ,AminoArylthiazole ,Corrector ,Docking ,Structure-Activity Relationship ,Chlorides ,Drug Discovery ,Humans ,Structure–activity relationship ,Binding site ,CFTR ,Pharmacology ,Chemistry ,Drug Discovery3003 Pharmaceutical Science ,SAR ,Organic Chemistry ,Biological Transport ,General Medicine ,Potentiator ,Small molecule ,Transmembrane protein ,Cell biology ,Protein Structure, Tertiary ,Thiazoles ,Cyclic nucleotide-binding domain ,Cystic fibrosi ,Drug Design ,Mutation ,Chloride channel ,Thiazole ,Ion Channel Gating ,Human - Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.
- Published
- 2015
94. Further insights into the pharmacology of the human trace amine-associated receptors: discovery of novel ligands for TAAR1 by a virtual screening approach
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Sara Guariento, Silvia Franchini, Paola Fossa, Livio Brasili, Raul R. Gainetdinov, Stefano Espinoza, and Elena Cichero
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human Trace Amine-Associated Receptors ,TAAR1 ,Drug Evaluation, Preclinical ,Pharmacology ,Biology ,Ligands ,Biochemistry ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Synthesis ,Drug Discovery ,Phenethylamines ,Fluorescence Resonance Energy Transfer ,Humans ,Receptor ,Trace amine ,Oxazoles ,human Trace Amine-Associated Receptors, TAAR1, virtual screening, Synthesis, ligands ,G protein-coupled receptor ,Virtual screening ,Binding Sites ,ligands ,Organic Chemistry ,EPPTB ,Octopamine (drug) ,RO5166017 ,virtual screening ,Protein Structure, Tertiary ,Molecular Docking Simulation ,HEK293 Cells ,chemistry ,Molecular Medicine ,Databases, Chemical ,Protein Binding - Abstract
Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor that is expressed in brain and periphery and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA), tyramine, tryptamine, octopamine. The receptor is known to have a very rich pharmacology and could be also activated by different classes of compounds, including dopaminergic, adrenergic and serotonergic ligands. It is expected that targeting hTAAR1 could provide a novel pharmacological approach for several human disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder, Parkinson's disease and metabolic diseases. Only recently, a small number of selective hTAAR1 agonists (among which RO5166017 and T1 AM) and antagonist (EPPTB), have been reported in literature. With the aim to identify new molecular entities able to act as ligands for this target, we used an homology model for the hTAAR1 and performed a virtual screening procedure on an in-house database of compounds. A number of interesting molecules were selected and by testing them in an in vitro assay we found several agonists and one antagonist, with activities in the low micromolar range. These compounds could represent the starting point for the development of more potent and selective TAAR1 ligands.
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- 2014
95. Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors
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Elena Cichero, Anna Maria Baraldi, Paola Fossa, Livio Brasili, Annalisa Tait, Silvia Franchini, Umberto Maria Battisti, Antonio Cilia, Claudia Sorbi, Adolfo Prandi, Lorenza Pirona, and Gabriella Marucci
- Subjects
Agonist ,Protein Conformation ,Stereochemistry ,medicine.drug_class ,1,3-Dioxolane ,5-HT(1A)R ,Arylpiperazine derivatives ,Structure–affinity/activity relationships ,1+receptor%22">α ,1 receptor Decane ,Ligands ,Structure-Activity Relationship ,chemistry.chemical_compound ,Receptors, Adrenergic, alpha-1 ,Alkanes ,Drug Discovery ,medicine ,Humans ,Spiro Compounds ,Receptor ,5-HT receptor ,Pharmacology ,Organic Chemistry ,General Medicine ,Highly selective ,Ligand (biochemistry) ,Combinatorial chemistry ,Molecular Docking Simulation ,Piperazine ,chemistry ,Receptor, Serotonin, 5-HT1A ,Functional activity - Abstract
Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and αalpha1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising αalpha1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective αalpha1 or 5-HT1AR ligands.
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- 2014
96. Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modeling and docking studies
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Elena, Cichero, Stefano, Espinoza, Raul R, Gainetdinov, Livio, Brasili, and Paola, Fossa
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Molecular Docking Simulation ,Binding Sites ,Amino Acid Sequence ,Humans ,Molecular Sequence Data ,Oxazoles ,Phenethylamines ,Protein Structure, Tertiary ,Receptor, Serotonin, 5-HT1A ,Receptors, G-Protein-Coupled ,Sequence Alignment ,Thyronines - Abstract
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.
- Published
- 2013
97. Cover Picture: Impaired Chaperone Activity of Human Heat Shock Protein Hsp27 Site-Specifically Modified with Argpyrimidine (Angew. Chem. Int. Ed. 38/2016)
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Elena Cichero, Maria Matveenko, Paola Fossa, and Christian F. W. Becker
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biology ,INT ,Biological activity ,General Chemistry ,Catalysis ,chemistry.chemical_compound ,chemistry ,Hsp27 ,Biochemistry ,Heat shock protein ,biology.protein ,Argpyrimidine ,Cover (algebra) ,Chaperone activity - Published
- 2016
98. Titelbild: Impaired Chaperone Activity of Human Heat Shock Protein Hsp27 Site-Specifically Modified with Argpyrimidine (Angew. Chem. 38/2016)
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Maria Matveenko, Christian F. W. Becker, Elena Cichero, and Paola Fossa
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chemistry.chemical_compound ,Hsp27 ,biology ,Chemistry ,Heat shock protein ,biology.protein ,Biophysics ,Argpyrimidine ,General Medicine ,Chaperone activity - Published
- 2016
99. Scouting new molecular targets for CFTR therapy: the HSC70/BAG-1 complex. A computational study
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Mauro Mazzei, Anna Basile, Elena Cichero, Paola Fossa, and Maria Caterina Turco
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congenital, hereditary, and neonatal diseases and abnormalities ,animal structures ,biology ,HSC70 ,Chemistry ,In silico ,Organic Chemistry ,Pharmacology toxicology ,computational study ,macromolecular substances ,Computational biology ,Bioinformatics ,BAG-1 ,respiratory tract diseases ,Ubiquitin ,embryonic structures ,Molecular targets ,biology.protein ,CFTR ,General Pharmacology, Toxicology and Pharmaceutics ,Amino acid residue - Abstract
HSC70 has been identified as an important molecular target involved in the ΔF508-CFTR cystic fibrosis. HSC70 associates ΔF508-CFTR to a much greater extent than WT-CFTR and after this step, it recruits other co-chaperones (BAG1, CHIP) and performs the ubiquitination and proteosomal degradation of the protein. Up to now, several X-ray data concerning the HSC70:BAG1 complexes are available. Thus, we performed an “in silico” investigation focused to explore which different amino acid residues are involved in the binding of ATP, the natural substrate, and the co-crystallized ligands at the HSC70/BAG-1 interface. The study allowed us to evaluate sildenafil and KM11060, which proved to be also CFTR correctors, as potential HSC70:BAG1 inhibitors, and also let us derive interesting perspectives for the development of new CFTR correctors.
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- 2012
100. Docking-based 3D-QSAR analyses of pyrazole derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors
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Elena Cichero and Paola Fossa
- Subjects
Models, Molecular ,Quantitative structure–activity relationship ,CoMFA ,Stereochemistry ,Anti-HIV Agents ,Human immunodeficiency virus (HIV) ,Quantitative Structure-Activity Relationship ,HIV Infections ,Pyrazole ,Molecular Dynamics Simulation ,medicine.disease_cause ,Catalysis ,Nucleoside Reverse Transcriptase Inhibitor ,Docking ,Inorganic Chemistry ,chemistry.chemical_compound ,HIV- 1 ,medicine ,Reverse transcriptase ,Potency ,Humans ,Computer Simulation ,Physical and Theoretical Chemistry ,3D-QSAR ,CoMSIA ,Pyrazoles ,Binding Sites ,Organic Chemistry ,Molecular medicine ,HIV Reverse Transcriptase ,Computer Science Applications ,Computational Theory and Mathematics ,chemistry ,Docking (molecular) ,HIV-1 ,Computer-Aided Design ,Reverse Transcriptase Inhibitors - Abstract
1,3,4,5-tetrasubstituted-pyrazoles (TPs) have been recently identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by docking-based comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), has been used to elucidate the atomic details of the RT/TP interactions and to identify the most important features impacting the TP antiretroviral activity. The final CoMSIA model resulted to be the more predictive, showing r (ncv) (2) = 0.97, r (cv) (2) = 0.723, SEE = 0.248, F = 240.291, and r(2) (pred) = 0.77. The results allowed us to obtain useful information for the design of new compounds with improved potency toward WT HIV-1 and also against clinically relevant resistant mutants.
- Published
- 2012
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