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Your search keyword '"La Pietra, V"' showing total 7 results
Start Over Author "La Pietra, V" Topic drug design
7 results on '"La Pietra, V"'

1. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis.

Author

Runfola M, Sestito S, Bellusci L, La Pietra V, D'Amore VM, Kowalik MA, Chiellini G, Gul S, Perra A, Columbano A, Marinelli L, Novellino E, and Rapposelli S

Subjects
Animals, Dose-Response Relationship, Drug, Hep G2 Cells, Humans, Male, Molecular Structure, Pyridazines chemical synthesis, Pyridazines chemistry, Rats, Rats, Inbred F344, Structure-Activity Relationship, Uracil chemical synthesis, Uracil chemistry, Uracil pharmacology, Drug Design, Pyridazines pharmacology, Thyroid Hormone Receptors beta agonists, Uracil analogs & derivatives
Abstract

Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Published
2020
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2. Design, synthesis, and biological evaluation of 1-phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as new glycogen synthase kinase-3β inhibitors.

Author

La Pietra V, La Regina G, Coluccia A, Famiglini V, Pelliccia S, Plotkin B, Eldar-Finkelman H, Brancale A, Ballatore C, Crowe A, Brunden KR, Marinelli L, Novellino E, and Silvestri R

Subjects
Cell Line, Dose-Response Relationship, Drug, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Humans, Indolizidines chemical synthesis, Indolizidines chemistry, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemistry, Recombinant Proteins metabolism, Structure-Activity Relationship, Succinimides chemical synthesis, Succinimides chemistry, Drug Design, Glycogen Synthase Kinase 3 antagonists & inhibitors, Indolizidines pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Succinimides pharmacology
Abstract

Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3β inhibitors. MC/FEP calculations of 5 led to the identification of a structural class of new GSK-3β inhibitors. Compound 18 inhibited GSK-3β with an IC50 of 0.24 μM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.

Published
2013
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3. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.

Author

La Pietra V, Marinelli L, Cosconati S, Di Leva FS, Nuti E, Santamaria S, Pugliesi I, Morelli M, Casalini F, Rossello A, La Motta C, Taliani S, Visse R, Nagase H, da Settimo F, and Novellino E

Subjects
Catalytic Domain, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Inhibitory Concentration 50, Matrix Metalloproteinase 13 chemistry, User-Computer Interface, Drug Design, Matrix Metalloproteinase Inhibitors, Protease Inhibitors chemistry, Protease Inhibitors pharmacology
Abstract

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Published
2012
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4. N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.

Author

Nuti E, Casalini F, Avramova SI, Santamaria S, Cercignani G, Marinelli L, La Pietra V, Novellino E, Orlandini E, Nencetti S, Tuccinardi T, Martinelli A, Lim NH, Visse R, Nagase H, and Rossello A

Subjects
ADAM Proteins chemistry, ADAM17 Protein, Cartilage metabolism, Hydroxamic Acids pharmacology, Hydroxamic Acids therapeutic use, Matrix Metalloproteinase 1 chemistry, Matrix Metalloproteinase 13 chemistry, Matrix Metalloproteinase 14 chemistry, Models, Molecular, Protease Inhibitors pharmacology, Protease Inhibitors therapeutic use, Structure-Activity Relationship, Drug Design, Hydroxamic Acids chemical synthesis, Matrix Metalloproteinase Inhibitors, Osteoarthritis drug therapy, Protease Inhibitors chemical synthesis
Abstract

Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.

Published
2009
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5. Protein Flexibility in Virtual Screening: The BACE-1 Case Study

Author

Vincenza Andrisano, Valeria La Pietra, David S. Goodsell, Angela De Simone, Sandro Cosconati, Luciana Marinelli, Francesca Mancini, Arthur J. Olson, Ettore Novellino, Francesco Saverio Di Leva, S., Cosconati, Marinelli, Luciana, Di Leva, Francesco Saverio, LA PIETRA, Valeria, A., De Simone, F., Mancini, V., Andrisano, Novellino, Ettore, D. S., Goodsell, A. J., Olson, Cosconati S., Marinelli L., Di Leva F.S., La Pietra V., De Simone A., Mancini F., Andrisano V., Novellino E., Goodsell D.S., Olson A.J., Cosconati, Sandro, Marinelli, L, Di Leva, F, La Pietra, V, De Simone, A, Mancini, F, Andrisano, V, Novellino, E, Goodsell, D, and Olson, A. J.

Subjects
STRUCTURE-BASED DESIGN, FLEXIBLE SIDE-CHAINS, MEMAPSIN-2 BETA-SECRETASE, APP CLEAVING ENZYME, DRUG DESIGN, MOLECULAR RECOGNITION, ALZHEIMERS-DISEASE, LIGAND DOCKING, SOFT DOCKING, ACTIVE-SITE, Protein Conformation, General Chemical Engineering, Library and Information Sciences, Machine learning, computer.software_genre, Crystallography, X-Ray, Ligands, Molecular Docking Simulation, Article, Antiparkinson Agents, User-Computer Interface, Alzheimer Disease, High-Throughput Screening Assays, Drug Discovery, Fluorescence Resonance Energy Transfer, Aspartic Acid Endopeptidases, Humans, Simulation, Virtual screening, Binding Sites, Chemistry, business.industry, Drug discovery, General Chemistry, Grid, Computer Science Applications, Weighting, Thermodynamics, Artificial intelligence, Amyloid Precursor Protein Secretases, business, computer, Algorithms, Databases, Chemical, Protein Binding
Abstract

Simulating protein flexibility is a major issue in the docking-based drug-design process for which a single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with the challenge of including receptor plasticity in a virtual screening campaign aimed at finding new β-secretase inhibitors. To this aim, we incorporated protein flexibility in our simulations by using an ensemble of static X-ray enzyme structures to screen the National Cancer Institute database. A unified description of the protein motion was also generated by computing and combining a set of grid maps using an energy weighting scheme. Such a description was used in an energy-weighted virtual screening experiment on the same molecular database. Assessment of the enrichment factors from these two virtual screening approaches demonstrated comparable predictive powers, with the energy-weighted method being faster than the ensemble method. The in vitro evaluation demonstrated that out of the 32 tested ligands, 17 featured the predicted enzyme inhibiting property. Such an impressive success rate (53.1%) demonstrates the enhanced power of the two methodologies and suggests that energy-weighted virtual screening is a more than valid alternative to ensemble virtual screening given its reduced computational demands and comparable performance. © 2012 American Chemical Society.

Published
2012

6. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis

Author

Amedeo Columbano, Grazia Chiellini, Luciana Marinelli, Ettore Novellino, Vincenzo Maria D'Amore, Marta Anna Kowalik, Massimiliano Runfola, Valeria La Pietra, Sheraz Gul, Lorenza Bellusci, Andrea Perra, Simona Sestito, Simona Rapposelli, Runfola, M., Sestito, S., Bellusci, L., La Pietra, V., D'Amore, V. M., Kowalik, M. A., Chiellini, G., Gul, S., Perra, A., Columbano, A., Marinelli, L., Novellino, E., and Rapposelli, S.

Subjects
Male, Thyronamine, Hep G2 Cell, Fatty-liver disorder, Liver regeneration, TRβ selective agonist, Triiodothyronine, Pharmacology, 01 natural sciences, Thyroid hormone receptor beta, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Animals, Humans, Uracil, 030304 developmental biology, ADME, 0303 health sciences, Thyroid hormone receptor, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Drug discovery, Animal, Organic Chemistry, Lipid metabolism, Thyroid Hormone Receptors beta, General Medicine, Hep G2 Cells, Rats, Inbred F344, 0104 chemical sciences, Rats, Pyridazines, chemistry, Drug Design, Toxicity, Rat, Pyridazine, Human
Abstract

Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as “potentially safe” to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics.

Published
2019

7. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization

Author

Valeria La Pietra, Sabrina Taliani, Hideaki Nagase, Elisa Nuti, Robert Visse, Federico Da Settimo, Francesco Saverio Di Leva, Ettore Novellino, Luciana Marinelli, Concettina La Motta, Salvatore Santamaria, Sandro Cosconati, Matteo Morelli, Armando Rossello, F Casalini, Isabella Pugliesi, La Pietra, V, Marinelli, L, Cosconati, Sandro, Di Leva, F, Nuti, E, Santamaria, S, Pugliesi, I, Morelli, M, Casalini, F, Rossello, A, La Motta, C, Taliani, S, Visse, R, Nagase, H, da Settimo, F, Novellino, E., LA PIETRA, Valeria, Marinelli, Luciana, Cosconati, S., Di Leva, Francesco Saverio, Nuti, E., Santamaria, S., Pugliesi, I., Morelli, M., Casalini, F., Rossello, A., La Motta, C., Taliani, S., Visse, R., Nagase, H., da Settimo, F., and Novellino, Ettore

Subjects
Virtual screening, High selectivity, Drug Evaluation, Preclinical, Nanotechnology, Articular cartilage, Osteoarthritis, Matrix Metalloproteinase Inhibitors, Matrix metalloproteinase, Crystallography, X-Ray, Inhibitory Concentration 50, User-Computer Interface, Catalytic Domain, Matrix Metalloproteinase 13, Drug Discovery, medicine, Humans, Protease Inhibitors, IC50, Cancer, Pharmacology, MMP, Chemistry, Cartilage, Organic Chemistry, General Medicine, medicine.disease, medicine.anatomical_structure, Docking (molecular), Drug Design, Molecular docking, Cancer research, Osteoarthriti
Abstract

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC 50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. © 2011 Elsevier Masson SAS. All rights reserved.

Published
2012

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