445 results on '"Pierre-Alain Carrupt"'
Search Results
2. Study of Leaf Metabolome Modifications Induced by UV-C Radiations in Representative Vitis, Cissus and Cannabis Species by LC-MS Based Metabolomics and Antioxidant Assays
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Guillaume Marti, Sylvain Schnee, Yannis Andrey, Claudia Simoes-Pires, Pierre-Alain Carrupt, Jean-Luc Wolfender, and Katia Gindro
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phytoalexins ,UV-C stress ,metabolomics ,LC-MS ,Cannabis sativa ,Cissus antarctica ,Vitis vinifera ,chemodiversity ,Organic chemistry ,QD241-441 - Abstract
UV-C radiation is known to induce metabolic modifications in plants, particularly to secondary metabolite biosynthesis. To assess these modifications from a global and untargeted perspective, the effects of the UV-C radiation of the leaves of three different model plant species, Cissus antarctica Vent. (Vitaceae), Vitis vinifera L. (Vitaceae) and Cannabis sativa L. (Cannabaceae), were evaluated by an LC-HRMS-based metabolomic approach. The approach enabled the detection of significant metabolite modifications in the three species studied. For all species, clear modifications of phenylpropanoid metabolism were detected that led to an increased level of stilbene derivatives. Interestingly, resveratrol and piceid levels were strongly induced by the UV-C treatment of C. antarctica leaves. In contrast, both flavonoids and stilbene polymers were upregulated in UV-C-treated Vitis leaves. In Cannabis, important changes in cinnamic acid amides and stilbene-related compounds were also detected. Overall, our results highlighted phytoalexin induction upon UV-C radiation. To evaluate whether UV-C stress radiation could enhance the biosynthesis of bioactive compounds, the antioxidant activity of extracts from control and UV-C-treated leaves was measured. The results showed increased antioxidant activity in UV-C-treated V. vinifera extracts.
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- 2014
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3. Molecular Docking Using the Molecular Lipophilicity Potential as Hydrophobic Descriptor: Impact on GOLD Docking Performance.
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Alessandra Nurisso, Juan Bravo, Pierre-Alain Carrupt, and Antoine Daina
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- 2012
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4. Computational studies on sirtuins from Trypanosoma cruzi: structures, conformations and interactions with phytochemicals.
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Lionel Sacconnay, Melissa Angleviel, Giuseppe Marco Randazzo, Marcos Marçal Ferreira Queiroz, Emerson Ferreira Queiroz, Jean-Luc Wolfender, Pierre-Alain Carrupt, and Alessandra Nurisso
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BACKGROUND: The silent-information regulator 2 proteins, otherwise called sirtuins, are currently considered as emerging anti-parasitic targets. Nicotinamide, a pan-sirtuin inhibitor, is known to cause kinetoplast alterations and the arrested growth of T. cruzi, the protozoan responsible for Chagas disease. These observations suggested that sirtuins from this parasite (TcSir2rp1 and TcSir2rp3) could play an important role in the regulation of the parasitic cell cycle. Thus, their inhibition could be exploited for the development of novel anti-trypanosomal compounds. METHODS: Homology modeling was used to determine the three-dimensional features of the sirtuin TcSir2rp1 from T. cruzi. The apo-form of human SIRT2 and the same structure solved in complex with its co-substrate NAD(+) allowed the modeling of TcSir2rp1 in the open and closed conformational states. Molecular docking studies were then carried out. A library composed of fifty natural and diverse compounds that are known to be active against this parasite, was established based on the literature and virtually screened against TcSir2rp1 and TcSir2rp3, which was previously modeled by our group. RESULTS: In this study, two conformational states of TcSir2rp1 were described for the first time. The molecular docking results of compounds capable of binding sirtuins proved to be meaningful when the closed conformation of the protein was taken into account for calculations. This specific conformation was then used for the virtual screening of antritrypanosomal phytochemicals against TcSir2rp1 and TcSir2rp3. The calculations identified a limited number of scaffolds extracted from Vismia orientalis, Cussonia zimmermannii, Amomum aculeatum and Anacardium occidentale that potentially interact with both proteins. CONCLUSIONS: The study provided reliable models for future structure-based drug design projects concerning sirtuins from T. cruzi. Molecular docking studies highlighted not only the advantages of performing in silico interaction studies on their closed conformations but they also suggested the potential mechanism of action of four phytochemicals known for their anti-trypanosomal activity in vitro.
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- 2014
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5. Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications.
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Patrick Gaillard, Pierre-Alain Carrupt, Bernard Testa, and Alain Boudon
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- 1994
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6. Analytical Strategy to Characterize Drug–Plasma Interactions: From High Throughput to In-depth Analysis
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Karine Vuignier, Jean-Luc Veuthey, Pierre-Alain Carrupt, and Julie Schappler
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Affinity chromatography ,Capillary electrophoresis ,Pharmacokinetics ,Protein interaction ,Surface plasmon resonance ,Chemistry ,QD1-999 - Published
- 2013
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7. How to Increase the Safety and Efficacy of Compounds against Neurodegeneration? A Multifunctional Approach
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Alessandra Nurisso, Claudia Simoes-Pires, Sophie Martel, Delphine Cressend, Amandine Guillot, and Pierre-Alain Carrupt
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Antioxidant activity ,Bioconcentration ,Hdac ,Neurodegeneration ,Chemistry ,QD1-999 - Abstract
Successful drug design requires not only the detailed knowledge of the pharmacokinetic and pharmacodynamic profiles of the drug candidate portfolio but also a thorough documentation of the possible toxic effects on humans and the environment. Thus, experimental and computational strategies able to measure or predict specific profiles of designed compounds related to their potential toxicity are highly desired. Moreover, a strategy to avoid toxic effects thus enhancing the potential efficacy of drug candidates is of great interest. To fulfil this aim, the pharmacochemistry research unit at the EPGL has recently developed and improved methodologies that detect the potential human health and environmental hazards of compounds active against neurodegeneration at an early stage. A three-step strategy is presented herein. In particular, i) an alternative index to model the bioconcentration of chemicals in the environment was determined; ii) the antioxidant activity of chemical species against free radicals was evaluated. Moreover, since antioxidants play a key role in both toxicity prevention and neuroprotection, iii) the potential interaction of such compounds with enzymatic targets involved in the neurodegenerative cascade was investigated in silico.
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- 2012
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8. The School of Pharmacy Geneva-Lausanne (EPGL) – The First Ten Years
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Gerrit Borchard and Pierre-Alain Carrupt
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School of pharmacy geneva-lausanne (epgl) ,Chemistry ,QD1-999 - Abstract
With the creation of the School of Pharmacy Geneva-Lausanne (EPGL) in 2003, cantons Geneva and Vaud pooled their resources with the objective of reinforcing the research and teaching in the pharmaceutical sciences. Its core research units cover all aspects of fundamental pharmaceutical research and include collaborative research with the University Hospitals of Geneva and Lausanne.
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- 2012
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9. Zebrafish bioassay-guided isolation of antiseizure compounds from the Cameroonian medicinal plant Cyperus articulatus L
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Jean-Luc Wolfender, Paul Herrling, Pierre-Alain Carrupt, Alexander D. Crawford, Elisabeth Ngo Bum, Maxime Jacmin, Charlotte Petit, Ivan Slacanin, Théo Brillatz, Emerson Ferreira Queiroz, and Laurence Marcourt
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Pharmacology ,0303 health sciences ,Traditional medicine ,Chemistry ,Pharmaceutical Science ,Decoction ,Sesquiterpene ,law.invention ,Rhizome ,Cyperus articulatus ,Hexane ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Complementary and alternative medicine ,law ,030220 oncology & carcinogenesis ,Drug Discovery ,Molecular Medicine ,Bioassay ,Medicinal plants ,Essential oil ,030304 developmental biology - Abstract
Background Epilepsy is a chronic neurological disorder affecting more than 50 million people worldwide, of whom 80% live in low- and middle-income countries. Due to the limited availability of antiseizure drugs (ASDs) in these countries, medicinal plants are the first-line treatment for most epilepsy patients. In Cameroon, a decoction of Cyperus articulatus L. rhizomes is traditionally used to treat epilepsy. Purpose The aim of this study was to identify and isolate the active compounds responsible for the antiseizure activity of C. articulatus in order to confirm both its traditional medicinal usage and previous in vivo studies on extracts of this plant in mouse epilepsy models. Methods The dried rhizomes of C. articulatus were extracted with solvents of increasing polaritie (hexane, dichloromethane, methanol and water). A traditional decoction and an essential oil were also prepared. These extracts were evaluated for antiseizure activity using a larval zebrafish seizure model with seizures induced by the GABAA antagonist pentylenetetrazole (PTZ). The hexane extract demonstrated the highest antiseizure activity and was therefore selected for bioassay-guided fractionation. The isolated bioactive compounds were characterized by classical spectroscopic methods. Since they were found to be volatile, they were quantified by GC-FID. In addition, the absorption of the active compounds through the gastrointestinal tract and the blood-brain barrier was evaluated using a hexadecane and a blood-brain barrier parallel artificial membrane permeability assays (HDM-PAMPA and PAMPA-BBB). Results The hexane extract of C. articulatus exhibited the highest antiseizure activity with a reduction of 93% of PTZ-induced seizures, and was therefore subjected to bioassay-guided fractionation in order to isolate the active principles. Four sesquiterpenoids were identified as cyperotundone (1), mustakone (2), 1,2-dehydro-α-cyperone (3) and sesquichamaenol (4) and exhibited significant antiseizure activity. These volatile compounds were quantified by GC in the hexane extract, the essential oil and the simulated traditional decoction. In addition, the constituents of the hexane extract including compounds 1 and 2 were found to cross the gastrointestinal barrier and the major compound 2 crossed the blood-brain barrier as well. Conclusion These results highlight the antiseizure activity of various sesquiterpene compounds from a hexane extract of C. articulatus dried rhizomes and support its use as a traditional treatment for epilepsy.
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- 2019
10. Stereoselective Block of hERG Channel by Bupivacaine Scrutinized at Molecular Level
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Liliana Sintra Grilo, Pierre-Alain Carrupt, and Antoine Daina
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Bupivacaine ,Cardiotoxicity ,Docking ,Herg-block ,Stereoselectivity ,Chemistry ,QD1-999 - Abstract
In the heart, the hERG voltage-gated potassium channel mediates the IKr current, which is crucial for the duration of cardiac action potential. Undesired block of the channel may prolong the QT interval with increased risk of malignant ventricular arrhythmia called torsades de pointes. Although the molecular determinants of hERG block are intensively studied, stereoselectivity has been poorly investigated. Levo-(S)-bupivacaine was the first drug reported to have higher affinity for hERG than its enantiomer. This study aims at understanding the principles underlying the stereoselectivity of bupivacaine block with the help of molecular modeling. Putative binding modes of levo-(S)- and dextro-(R)-bupivacaine inside an open form model of hERG channel were predicted by docking simulations, allowing a clear depiction of ligand-protein interactions. Estimated binding energies for both enantiomers to wild-type channel are in line with previously published electrophysiology measurements. These results may be considered as a confirmation at the molecular level of bupivacaine stereoselective binding towards hERG. Moreover this information lays the foundations for a structural guideline to filter out potentially cardiotoxic drug candidates in silico.
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- 2010
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11. Plant Metabolomics – Strategies for Biomarker Detection, Isolation, and Identification
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Elia Grata, Julien Boccard, Gaëtan Glauser, Davy Guillarme, Pierre-Alain Carrupt, Jean-Luc Wolfender, and Serge Rudaz
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Arabidopsis thaliana ,Capillary nmr ,Data mining ,Metabolomics ,Plant metabolism ,Stress-induced metabolites ,Chemistry ,QD1-999 - Published
- 2008
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12. Synergy at the 'Ecole de Pharmacie Genève-Lausanne': Methodology Developments for the Treatment of Complex Metabolomic Datasets with Data Mining
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Aly Thiocone, Elia Grata, Julien Boccard, Pierre-Alain Carrupt, Serge Rudaz, and Jean-Luc Wolfender
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Arabidopsis thaliana ,Data mining ,Lc/ms ,Metabolomic ,Chemistry ,QD1-999 - Abstract
With the advances in analytical techniques and data mining, the chances to elucidate a plant metabolome and understand the metabolite variation in response to external stimuli such as stress are gradually becoming feasible in a global manner. This approach represents a very important research challenge because of the structural diversity of the metabolites and the convolute nature of biological matrices. Based on a new collaborative framework emerging from the recent creation of the EPGL, a project aimed at the development of methodology for the treatment of complex metabolomic datasets with data mining has been initiated with the expertise of different EPGL laboratories. In this paper the strategies used for the study of the metabolic variations in a biological model (the effect of mechanical wounding on Arabidopsis thaliana) are described. Metabolite profiling based on micro-extraction and LC/MS analysis with various detection methods has been used. Data were parsed in the form of ion maps and treatment of this complex set of MS information was performed with dedicated bioinformatic tools. This approach should enable the evaluation of metabolome variations in a comprehensive manner for a better understanding of complex biological mechanisms and for the detection of novel bioactive molecules.
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- 2005
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13. Experimental and Virtual Physicochemical and Pharmacokinetic Profiling of New Chemical Entities
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Sophie Martel, Marc-Etienne Castella, Fania Bajot, Giorgio Ottaviani, Bruno Bard, Yveline Henchoz, Bénédicte Gross Valloton, Marianne Reist, and Pierre-Alain Carrupt
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In vitro intestinal perfusion model ,Pampa technique ,Pharmacokinetic profiling ,Physicochemical profiling ,3d solvatochromic model ,Chemistry ,QD1-999 - Abstract
Physicochemical and pharmacokinetic profiling of new chemical entities (NCEs) allows the rapid identification and elimination of compounds with properties not suitable for further development as drug candidates. Among the complex panel of theoretical and experimental methods available to predict or measure physicochemical or pharmacokinetic properties, some key techniques developed or tested in the pharmacochemistry group at EPGL are presented. This paper focuses on virtual and experimental approaches dealing with key properties such as ionization, solubility, lipophilicity, and membrane permeation. In addition, the effect of the third dimension on intramolecular interactions is exemplified by lipophilicity variations in the conformational space of cyclosporin A and with a 3D solvatochromic model able to accurately predict the BBB permeation.
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- 2005
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14. Identification of Novel Multifunctional Compounds for the Treatment of Some Aging Related Neurodegenerative Diseases
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Laura Novaroli, Antoine Daina, Francesca Bertolini, Saviana Di Giovanni, Juan Bravo, Marianne Reist, and Pierre-Alain Carrupt
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Acetylcholinesterase ,Experimental screening ,Monoamine oxidase b ,Neurodegenerative diseases ,Virtual screening ,Chemistry ,QD1-999 - Abstract
Aging related neurodegenerative disorders such as Parkinson disease (PD) and Alzheimer's disease (AD) are the result of multiple pathophysiological pathways that contribute to the neurodegenerative cascade. Hence, multifunctional drug candidates able to interact with several targets are of great interest for the treatment of such diseases. Therefore, an experimental and virtual screening pathway to generate multifunctional hits showing promise for the treatment of PD or AD was suggested. Moreover, suitable experimental and virtual screening methods to rapidly test pre-focused compound libraries were developed and validated. In particular, the screening was focused on potential inhibitors of acetylcholinesterase (AChE) and monoamine oxidase B (MAO B) using a combination of in vitro enzymatic tests, docking and scoring approaches and refined molecular modeling tools.
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- 2005
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15. The Medicinal Chemist's Dream: Faster Design of Better and Safer Drug Candidates
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Marianne Reist, Laura Novaroli, Antoine Daina, Sophie Martel, and Pierre-Alain Carrupt
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Focused libraries ,Hit generation ,In vitro screening ,Lead generation ,Virtual screening ,Chemistry ,QD1-999 - Abstract
Successful drug research depends on adequate links between therapeutic benefits for the treatment of a disease, pertinent biological targets and suitable chemical compounds. The pharmacochemistry group at EPGL is active in the development of virtual and experimental methods to enhance these links following a general hit and lead generation strategy to reduce large chemically diverse databases to lead collections. This strategy is based on a careful definition of its numerous steps and on a series of key validation processes. Particular attention is devoted to identify and improve the usefulness of virtual screening techniques widely used in drug development. The guidelines proposed here to use the best validated tools in the most suitable order will help the medicinal chemist to approach his dream, namely to be faster in the design of better and safer drug candidates.
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- 2005
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16. Editorial
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Pierre-Alain Carrupt and Robert Gurny
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Chemistry ,QD1-999 - Published
- 2005
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17. HDM-PAMPA to predict gastrointestinal absorption, binding percentage, equilibrium and kinetics constants with human serum albumin and using 2 end-point measurements
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Julie Schappler, Serge Rudaz, Charlotte Petit, Alban Bujard, and Pierre-Alain Carrupt
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Absorption (pharmacology) ,Cell Membrane Permeability ,Endpoint Determination ,Kinetics ,Synthetic membrane ,Pharmaceutical Science ,Hexadecane ,030226 pharmacology & pharmacy ,01 natural sciences ,Dissociation (chemistry) ,Dissociation/association microconstants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alkanes ,Passive permeability ,medicine ,Humans ,Serum Albumin ,Dissociation/association constants ,ddc:615 ,Chromatography ,Gastrointestinal tract absorption ,Chemistry ,010401 analytical chemistry ,Human serum albumin ,Membranes, Artificial ,Biological membrane ,0104 chemical sciences ,PAMPA ,Gastrointestinal Absorption ,Permeability (electromagnetism) ,Binding percentage ,Forecasting ,Protein Binding ,medicine.drug - Abstract
The parallel artificial membrane permeability assay (PAMPA) is a high-throughput screening (HTS) technique developed to predict passive permeability through numerous different biological membranes, such as the gastrointestinal tract (GIT), the blood brain barrier (BBB), and the dermal layer. PAMPA is based on an artificial membrane, such as hexadecane (HDM), which separates two compartments (i.e., a donor and an acceptor compartment). In the present study, an HDM-PAMPA method was developed with human serum albumin (HSA) under iso-pH and gradient-pH conditions to predict the percentage of binding, dissociation/association constants (Kd and Ka, respectively) and dissociation/association kinetic rates (koff and kon, respectively) between a given drug and HSA. Thanks to the kinetic properties of PAMPA, a two end-point assay was implemented to obtain all three properties. The assay was used to measure basic, acidic, and amphoteric compounds. The protein was free in solution, allowing a direct comparison between this assay and equilibrium dialysis (ED). The developed PAMPA enabled screening of up to 96 compounds in a single run, generating valuable information on absorption and distribution in a high-throughput and high-repeatable manner.
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- 2017
18. An Effective Tool for Column Evaluation in the Analysis of Basic Compounds
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Cinzia Stella, Patrick Seuret, Serge Rudaz, Pierre-Alain Carrupt, Jean-Yves Gauvrit, Pierre Lanteri, and Jean-Luc Veuthey
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Basic compounds ,Chromatographic test ,High-performance liquid chromatography ,Principal component analysis ,Chemistry ,QD1-999 - Abstract
A chromatographic test is described for the evaluation of base-deactivated stationary phases. Seven test basic compounds, selected on their physico-chemical properties, were injected with two different mobile phases (one at pH 7.0 and the other at pH 3.0), on 45 chromatographic supports. Thanks to the measured chromatographic parameters (k and As), it was possible to evaluate both silanol activity and hydrophobic character of the base-deactivated columns. In addition, the validity of this chromatographic test was assessed by measuring the fundamental properties of the same supports with a general test protocol, issued from the literature.
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- 2003
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19. MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design
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Pierre-Alain Carrupt, Nils Oberhauser, and Alessandra Nurisso
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Computer science ,business.industry ,Python (programming language) ,Machine learning ,computer.software_genre ,Lipids ,Computer Science Applications ,Visualization ,Computational science ,Open source ,Docking (molecular) ,Drug Design ,Drug Discovery ,Lipophilicity ,Computer-aided ,Computer-Aided Design ,Computer Aided Design ,Plug-in ,Artificial intelligence ,Physical and Theoretical Chemistry ,business ,Hydrophobic and Hydrophilic Interactions ,computer ,computer.programming_language - Abstract
The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub-program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples.
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- 2019
20. Lipophilicity and Related Molecular Properties as Determinants of Pharmacokinetic Behaviour
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Bernard Testa, Giulia Caron, Patrizia Crivori, Sébastien Rey, Marianne Reist, and Pierre Alain Carrupt
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Hydrogen bonding capacity ,Intramolecular interactions ,Intermolecular forces ,Lipophilicity ,Pharmaceutical chemistry ,Pharmacokinetic behaviour ,Chemistry ,QD1-999 - Abstract
This minireview presents some recent work, mainly from the authors' laboratory, aimed at improving the interpretability and predictivity of structure-pharmacokinetic relationships. The first part of the text discusses the intermolecular forces and intramolecular interactions encoded in lipophilicity, with emphasis on the hydrogen-bonding capacity of bioactive compounds. Three-dimensional molecular fields provide a most informative and relevant description of molecular structure and properties, particularly the Molecular Lipophilicity Potential (MLP) and our novel Molecular Hydrogen Bonding Potentials (MHBPs), both of which are computed from experimentally derived atomic increments.The second part of the paper discusses selected structure-pharmacokinetic relations, illustrating how permeation processes are influenced by the H-bonding capacity of permeants. Thus, lipophilicity-derived H-bonding parameters are found to correlate with skin permeation and brain penetration. Similarly, the donor MHBP provides a promising correlation with oral absorption data in humans.Although structure-metabolism relations are not discussed here, we summarise investigations showing how metabolic N-oxygenation modifies the physicochemical properties of pyridines and tertiary arylalkylamines, and hence may influence their distribution and excretion.
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- 2000
21. Limits of rapid log P determination methods for highly lipophilic and flexible compounds
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William Schuler, Nils Oberhauser, Sophie Martel, Frédéric Begnaud, Fabrice Gillerat, Pierre-Alain Carrupt, and Alessandra Nurisso
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Models, Molecular ,0301 basic medicine ,Chromatography ,Chemistry ,010401 analytical chemistry ,Lipids ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Analytical Chemistry ,Partition coefficient ,03 medical and health sciences ,030104 developmental biology ,Lipophilicity ,Environmental Chemistry ,Determination methods ,Molecule ,Chromatography, High Pressure Liquid ,Spectroscopy - Abstract
Lipophilicity is of crucial importance in many fields including pharmaceutical, environmental, cosmetic and food industries. Whereas different experimental strategies have been developed for rapid lipophilicity determination of new chemical entities, log P determination of highly lipophilic compounds is always challenging. In this study, three published chromatographic methods have been compared on a series of phenylalkanoic acids including the pro-perfume HaloscentD (HD-C12). Different log P values were obtained depending on the chromatographic method used for log P estimation. Molecular modelling suggested that log P variations may be due to the chromatographic conditions applied (isocratic or gradient mode, ratio methanol/water in the mobile phase), responsible of specific conformations of the molecule in solution. Thus, for flexible compounds, published methods have to be used with caution and considered as a good tool to estimate a log P range, depending on the molecular conformational state.
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- 2016
22. 5-Benzylidene-hydantoin is a new scaffold for SIRT inhibition: From virtual screening to activity assays
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Carolina dos Santos Passos, Pierre-Alain Carrupt, Daumantas Matulis, Alessandra Nurisso, Jelena Jachno, Lucie Ryckewaert, Claudia A. Simões-Pires, Lionel Sacconnay, Giuseppe Marco Randazzo, Vilma Michailovienė, Asta Zubrienė, and Charlotte Petit
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0301 basic medicine ,Pharmaceutical Science ,Hydantoin ,SIRT2 ,Benzylidene Compounds ,HeLa ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Humans ,Sirtuins ,ADME ,chemistry.chemical_classification ,Virtual screening ,biology ,Hydantoins ,Lysine ,Acetylation ,biology.organism_classification ,Histone Deacetylase Inhibitors ,Kinetics ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,NAD+ kinase ,HeLa Cells - Abstract
Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of SIRTs catalytic activity was recently reported in the literature as being beneficial in human diseases, with very promising applications in cancer therapy and enzymatic neurodegeneration. By combining a structure-based virtual screening of the Specs database with cell-based assays, we identified the 5-benzylidene-hydantoin as new scaffold for the inhibition of SIRT2 catalytic activity. Compound 97 (Specs ID AH-487/41657829), active in the low μM range against SIRT2, showed the optimal physicochemical properties for passive absorption as well as relatively low cytotoxicity in vitro. Further studies revealed non-competitive and mixed-type kinetics toward acetyl-lysine substrates and NAD(+), respectively, and a non-selective profile for SIRT inhibition. A binding mode consistent with the experimental evidence was proposed by molecular modeling. Additionally, the levels of acetyl-p53 were shown to be increased in HeLa cells treated with 97. Taken together, these results encourage further investigation of 5-benzylidene-hydantoin derivatives for their SIRT-related therapeutic effects.
- Published
- 2016
23. Rapid determination of p K a values of 20 amino acids by CZE with UV and capacitively coupled contactless conductivity detections
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Laurent Geiser, Julie Schappler, Pierre-Alain Carrupt, Josiane Prat, Yveline Henchoz, and Jean-Luc Veuthey
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Conductometry ,Analytical chemistry ,Electro-osmosis ,Conductivity ,Amino Acids/analysis ,Biochemistry ,Analytical Chemistry ,Capillary electrophoresis ,A value ,Amino Acids ,Electrophoresis, Capillary/instrumentation/methods ,chemistry.chemical_classification ,ddc:615 ,Chromatography ,Spectrophotometry, Ultraviolet/methods ,Chemistry ,Osmolar Concentration ,Electric Conductivity ,Temperature ,Electrophoresis, Capillary ,Reproducibility of Results ,Hydrogen-Ion Concentration ,Models, Theoretical ,Amino acid ,Dissociation constant ,Ionic strength ,Spectrophotometry, Ultraviolet ,Electroosmosis - Abstract
A rapid and universal capillary zone electrophoresis (CZE) method was developed to determine the dissociation constants (pK a) of the 20 standard proteogenic amino acids. Since some amino acids are poorly detected by UV, capacitively coupled contactless conductivity detection (C4D) was used as an additional detection mode. The C4D coupling proved to be very successful on a conventional CE-UV instrument, neither inducing supplementary analyses nor instrument modification. In order to reduce the analysis time for pK a determination, two strategies were applied: (i) a short-end injection to reduce the effective length, and (ii) a dynamic coating procedure to generate a large electroosmotic flow (EOF), even at pH values as low as 1.5. As a result, the analysis time per amino acid was less than 2h, using 22 optimized buffers covering a pH range from 1.5 to 12.0 at a constant ionic strength of 50mM. pK a values were calculated using an appropriate mathematical model describing the relationship between effective mobility and pH. The obtained pK a values were in accordance with the literature. Figure a UV (1) and C4D (2) detectors placed on-line on the CE capillary. b Curve of effective mobility as a function of pH for histidine
- Published
- 2018
24. Comparison of the Performances of the Gaussian and Cadpac ab initio Program Packages on Different Computers
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Thomas Bally, Pierre-Alain Carrupt, and Jacques Weber
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Chemistry ,QD1-999 - Abstract
Ten different benchmark tests have been performed for different versions of the Gaussian as well as for the Cadpac ab initio program package on nine different computers ranging from vector supercomputers to workstations. The test jobs form a set representative of the most frequent applications of ab initio quantum chemistry, i.e. single point and gradient calculations at the SCF and MP2 levels of theory as well as SCF second derivative calculations for both closed-shell and open-shell species (the molecule of bicyclobutane and its radical cation calculated using the 6-31 G basis set). The relative performances of the different programs and machines exhibit considerable variation as a function of the type of calculation and the present results should prove useful for the selection of the most efficient program and computer for a given application. Notably, modem RISC-based workstations were found to be similar or sometimes even superior in performance to most mainframes for calculations of the type represented by the test jobs.
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- 1991
25. Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line
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Philippe Vayer, Jean Michel Scherrmann, Hélène Chapy, Pierre-Alain Carrupt, Gabriele Cruciani, Laura Goracci, Salvatore Cisternino, Xavier Declèves, and Yannick Parmentier
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Pharmacology ,Drug ,Virtual screening ,In vivo ,Chemistry ,media_common.quotation_subject ,Antiporter ,Transporter ,Human Metabolome Database ,Pharmacophore ,Drug metabolism ,media_common - Abstract
Background and purpose An influx drug/proton antiporter of unknown structure has been functionally demonstrated at the blood-brain barrier. This transporter, which handles some psychoactive drugs like diphenhydramine, clonidine, oxycodone, nicotine and cocaine, could represent a new pharmacological target in drug addiction therapy. However, at present there are no known drugs/inhibitors that effectively inhibit/modulate this transporter in vivo. Experimental approach The FLAPpharm approach was used to establish a pharmacophore model for inhibitors of this transporter. The inhibitory potency of 44 selected compounds was determined against the specific substrate, [(3)H]-clonidine, in the human cerebral endothelial cell line hCMEC/D3 and ranked as good, medium, weak or non-inhibitor. Key results The pharmacophore model obtained was used as a template to screen xenobiotic and endogenous compounds from databases [Specs, Recon2, Human Metabolome Database (HMDB), human intestinal transporter database], and hypothetical candidates were tested in vitro to determine their inhibitory capacity with [(3)H]-clonidine. According to the transporter database, 80% of the proton antiporter inhibitor candidates could inhibit P-glycoprotein/MDR1/ABCB1 and specificity is improved by reducing inhibitor size/shape and increasing water solubility. Virtual screening results using HMDB and Recon2 for endogenous compounds appropriately scored tryptamine as an inhibitor. Conclusions and implications The pharmacophore model for the proton-antiporter inhibitors was a good predictor of known inhibitors and allowed us to identify new good inhibitors. This model marks a new step towards the discovery of this drug/proton antiporter and will be of great use for the discovery and design of potent inhibitors that could potentially help to assess and validate its pharmacological role in drug addiction in vivo.
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- 2015
26. Inhibition screening method of microsomal UGTs using the cocktail approach
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Pierre-Alain Carrupt, Laurent Geiser, Julieta Gradinaru, Dany Spaggiari, Stéphanie Anne Romand, and Serge Rudaz
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Cocktail approach ,UGT1A4 ,Phase II metabolism ,Electrospray ionization ,Glucuronidation ,Pharmaceutical Science ,UHPLC–TOF ,Trifluoperazine ,digestive system ,chemistry.chemical_compound ,Glucuronides ,Chenodeoxycholic acid ,Human liver microsomes ,medicine ,Humans ,Enzyme Inhibitors ,Glucuronosyltransferase ,chemistry.chemical_classification ,ddc:615 ,Chromatography ,UGT2B7 ,Enzyme ,chemistry ,Microsomes, Liver ,Microsome ,UGT inhibition ,medicine.drug - Abstract
A rapid method for the simultaneous determination of the in vitro activity of the 10 major human liver UDP-glucuronosyltransferase (UGT) enzymes was developed based on the cocktail approach. Specific substrates were first selected for each UGT: etoposide for UGT1A1, chenodeoxycholic acid for UGT1A3, trifluoperazine for UGT1A4, serotonin for UGT 1A6, isoferulic acid for UGT1A9, codeine for UGT2B4, azidothymidine for UGT2B7, levomedetomidine for UGT2B10, 4-hydroxy-3-methoxymethamphetamine for UGT2B15 and testosterone for UGT2B17. Optimal incubation conditions, including time-based experiments on cocktail metabolism in pooled HLMs that had been performed, were then investigated. A 45- min incubation period was found to be a favorable compromise for all the substrates in the cocktail. Ultra-high pressure liquid chromatography coupled to an electrospray ionization time-of-flight mass spectrometer was used to separate the 10 substrates and their UGT-specific glucuronides in less than 6 min. The ability of the cocktail to highlight the UGT inhibitory potential of xenobiotics was initially proven by using well-known UGT inhibitors (selective and nonselective) and then by relating some of the screening results obtained by using the cocktail approach with morphine glucuronidation (substrate highly glucuronidated by UGT 2B7). All the results were in agreement with both the literature and with the expected effect on morphine glucuronidation.
- Published
- 2015
27. Retention time prediction for dereplication of natural products (CxHyOz) in LC–MS metabolite profiling
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Sophie Martel, Jean-Luc Wolfender, Benjamin Debrus, Philippe J. Eugster, Lise Bréant, Julien Boccard, and Pierre-Alain Carrupt
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Models, Molecular ,Biological Products ,Analyte ,Chromatography ,Databases, Factual ,Molecular Structure ,Metabolite ,Panax ,Plant Science ,General Medicine ,Horticulture ,Mass spectrometry ,Biochemistry ,chemistry.chemical_compound ,Metabolomics ,Italy ,chemistry ,Liquid chromatography–mass spectrometry ,Metabolite profiling ,Prediction methods ,Molecular Biology ,Retention time ,Algorithms ,Chromatography, High Pressure Liquid - Abstract
The detection and early identification of natural products (NPs) for dereplication purposes require efficient, high-resolution methods for the profiling of crude natural extracts. This task is difficult because of the high number of NPs in these complex biological matrices and because of their very high chemical diversity. Metabolite profiling using ultra-high pressure liquid chromatography coupled to high-resolution mass spectrometry (UHPLC–HR-MS) is very efficient for the separation of complex mixtures and provides molecular formula information as a first step in dereplication. This structural information alone or even combined with chemotaxonomic information is often not sufficient for unambiguous metabolite identification. In this study, a representative set of 260 NPs containing C, H, and O atoms only was analysed in generic UHPLC–HR-MS profiling conditions. Two easy to use quantitative structure retention relationship (QSRR) models were built based on the measured retention time and on eight simple physicochemical parameters calculated from the structures. First, an original approach using several partial least square (PLS) regressions according to the phytochemical classes provided satisfactory results with an easy calculation. Secondly, a unique artificial neural network (ANN) model provided similar results on the whole set of NPs but required dedicated software. The retention prediction methods described in this study were found to improve the level of confidence of the identification of given analytes among putative isomeric structures. Its applicability was verified for the dereplication of NPs in model plant extracts.
- Published
- 2014
28. Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study
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Pierre-Alain Carrupt, Joëlle Houriet, Laura Goracci, Charlotte Petit, Philippe Christen, Jean-Luc Wolfender, Sylvian Cretton, Martina Ceccarelli, and Krystyna Skalicka-Woźniak
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natural products ,PH permeability profile ,Phytochemicals ,Flavonoid ,Secondary Metabolism ,Pharmaceutical Science ,030226 pharmacology & pharmacy ,01 natural sciences ,Permeability ,Intestinal absorption ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Intestine, Small ,Drug Discovery ,Humans ,Organic chemistry ,Solubility ,passive intestinal absorption ,Secondary metabolism ,Pharmacology ,chemistry.chemical_classification ,Biological Products ,ddc:615 ,Natural products ,Chromatography ,secondary metabolites ,Drug Discovery3003 Pharmaceutical Science ,Secondary metabolites ,Organic Chemistry ,Glycoside ,Membranes, Artificial ,FaSSIF ,Complementary and Alternative Medicine2708 Dermatology ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Intestinal Absorption ,Complementary and alternative medicine ,chemistry ,pH permeability profile ,Lipophilicity ,Molecular Medicine ,Passive intestinal absorption ,Caco-2 Cells ,Natural Product Research ,solubility ,3003 - Abstract
Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.
- Published
- 2017
29. cIEF for rapid pKa determination of small molecules: A proof of concept
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Stéphanie Anne Romand, Jean-Luc Veuthey, Pierre-Alain Carrupt, Julie Schappler, and Sophie Martel
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Glycerol ,ddc:615 ,CIEF ,Chromatography ,Aqueous medium ,Capillary action ,Chemistry ,Isoelectric focusing ,Pharmaceutical Science ,Hydrogen-Ion Concentration ,Capillary isoelectric focusing ,Small molecule ,Acid dissociation constant ,Molecular Weight ,Small Molecule Libraries ,Coating ,chemistry.chemical_compound ,Ionization constant ,Ionization ,Isoelectric Focusing ,Cellulose - Abstract
A capillary isoelectric focusing (cIEF) method was developed for the determination of the ionization constants (pKa) of small molecules. Two approaches used to decrease the electroosmotic flow (EOF) were compared: (i) a hydroxypropylcellulose (HPC) coated capillary in aqueous medium and (ii) the addition of glycerol to act as a viscosifying agent. The cIEF method with the glycerol medium was selected, and the ionization constants of 22 basic and 21 acidic compounds, including 15 pharmaceutical drugs, were determined, resulting in pKa values from 3.5 to 7.4 and 6.4 to 9.3, respectively. cIEF offers an interesting alternative to other techniques for pKa determination with low sample consumption, high throughput and low cost.
- Published
- 2014
30. Non-specific SIRT inhibition as a mechanism for the cytotoxicity of ginkgolic acids and urushiols
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Pierre-Alain Carrupt, Alessandra Nurisso, Lucie Ryckewaert, Lionel Sacconnay, and Claudia A. Simões-Pires
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Models, Molecular ,Protein Conformation ,In silico ,Catechols ,General Medicine ,Biology ,Toxicology ,SIRT2 ,Salicylates ,In vitro ,Anacardic acids ,Molecular Docking Simulation ,chemistry.chemical_compound ,HEK293 Cells ,Sirtuin 2 ,Sirtuin 1 ,Biochemistry ,chemistry ,Apoptosis ,Catalytic Domain ,Toxicity ,Humans ,Cytotoxicity ,Carcinogen ,HeLa Cells - Abstract
Ginkgolic acids and urushiols are natural alkylphenols known for their mutagenic, carcinogenic and genotoxic potential. However, the mechanism of toxicity of these compounds has not been thoroughly elucidated so far. Considering that the SIRT inhibitory potential of anacardic acids has been hypothesized by in silico techniques, we herein demonstrated through both in vitro and computational methods that structurally related compounds such as ginkgolic acids and urushiols are able to modulate SIRT activity. Moreover, their SIRT inhibitory profile and cytotoxicity were comparable to sirtinol, a non-specific SIRT inhibitor (SIRT1 and SIRT2), and different from EX-527, a SIRT1 specific inhibitor. This is the first report on the SIRT inhibition of ginkgolic acids and urushiols. The results reported here are in line with previously observed effects on the induction of apoptosis by this class of compounds, and the non-specific SIRT inhibition is suggested as a new mechanism for their in vitro cytotoxicity.
- Published
- 2014
31. Collateral sensitivity of resistant MRP1-overexpressing cells to flavonoids and derivatives through GSH efflux
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Pierre-Alain Carrupt, Sandrine Magnard, Attilio Di Pietro, Claudia A. Simões-Pires, Raphaël Terreux, Estelle Genoux-Bastide, Hélène Baubichon-Cortay, Doriane Lorendeau, Ahcène Boumendjel, Lauriane Dury, and Florine Lecerf-Schmidt
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Quantitative Structure-Activity Relationship ,Apoptosis ,Pharmacology ,Biochemistry ,Antioxidants ,Cell Line ,Small Molecule Libraries ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Multidrug Resistance Protein 1 ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Cytotoxic T cell ,Chrysin ,Cytotoxicity ,Cell Proliferation ,Flavonoids ,Biological Transport ,Glutathione ,Antineoplastic Agents, Phytogenic ,Drug Resistance, Multiple ,Recombinant Proteins ,Neoplasm Proteins ,Up-Regulation ,chemistry ,Drug Resistance, Neoplasm ,Cancer cell ,Efflux ,Multidrug Resistance-Associated Proteins - Abstract
The multidrug resistance protein 1 (MRP1) is involved in multidrug resistance of cancer cells by mediating drug efflux out of cells, often in co-transport with glutathione (GSH). GSH efflux mediated by MRP1 can be stimulated by verapamil. In cells overexpressing MRP1, we have previously shown that verapamil induced a huge intracellular GSH depletion which triggered apoptosis of the cells. That phenomenon takes place in the more global anticancer strategy called "collateral sensitivity" and could be exploited to eradicate some chemoresistant cancer cells. Seeking alternative compounds to verapamil, we screened a library of natural flavonoids and synthetic derivatives. A large number of these compounds stimulate MRP1-mediated GSH efflux and the most active ones have been evaluated for their cytotoxic effect on MRP1-overexpressing cells versus parental cells. Interestingly, some are highly and selectively cytotoxic for MRP1-cells, leading them to apoptosis. However, some others do not exhibit any cytotoxicity while promoting a strong GSH efflux, indicating that GSH efflux is necessary but not sufficient for MRP1-cells apoptosis. In support to this hypothesis, structure activity relationships show that the absence of a hydroxyl group at position 3 of the flavonoid C ring is an absolute requirement for induction of MRP1-cells death, but is not for GSH efflux stimulation. Chrysin (compound 8) and its derivatives, compounds 11 and 22, exhibit a high selectivity toward MRP1-cells with a IC₅₀ value of 4.1 μM for compound 11 and 4.9 μM for chrysin and compound 22, making them among the best described selective killer compounds of multidrug ABC transporter-overexpressing cells.
- Published
- 2014
32. Modeling the Met Form of Human Tyrosinase: A Refined and Hydrated Pocket for Antagonist Design
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Antoine Daina, Alessandra Nurisso, Pierre-Alain Carrupt, and Elisabeth Favre
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Copper protein ,Stereochemistry ,Tyrosinase ,Molecular Sequence Data ,Biochemistry ,Molecular mechanics ,Catalytic Domain ,Drug Discovery ,Humans ,Molecule ,Amino Acid Sequence ,Homology modeling ,Enzyme Inhibitors ,Histidine ,Pharmacology ,biology ,Monophenol Monooxygenase ,Chemistry ,Organic Chemistry ,Active site ,Phenylthiourea ,Molecular Docking Simulation ,Structural Homology, Protein ,Docking (molecular) ,Drug Design ,biology.protein ,Molecular Medicine ,Sequence Alignment - Abstract
Tyrosinases are type 3 copper proteins involved in melanin biosynthesis, responsible for skin and hair color in mammals. To steer tyrosinase inhibitor discovery for therapeutic and cosmetic purposes, structural information about human tyrosinase is necessary. As this protein has never been crystallized so far, we derived a robust homology model built using structural information from Streptomyces castaneoglobisporus and Ipomea batata catecholoxidase enzymes. The active site containing two copper atoms in co-ordination with six histidine residues was refined through an optimization protocol based on molecular mechanics parameters for copper co-ordination and charges calculated by quantum mechanics methods. Five structural water molecules and a hydroxyl ion were found to be essential for optimization. The superimposition of the human homology model on crystallographic structures of tyrosinases from other species revealed similar overall backbone topologies, active site conformations, and conserved water molecules. Phenylthiourea (PTU), the tyrosinase inhibitor of reference, was then docked into the solvated human active pocket. A binding mode consistent with crystallographic information was obtained. Taken together, these findings demonstrated that the human tyrosinase model, deposited in the Protein Model Database, is a reliable structure for future rational inhibitor design projects.
- Published
- 2014
33. Indole Alkaloids and Semisynthetic Indole Derivatives as Multifunctional Scaffolds Aiming the Inhibition of Enzymes Related to Neurodegenerative Diseases – A Focus on Psychotria L. Genus
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Vinicius Galvao Wakui, Alessandra Nurisso, Carolina dos Santos Passos, Aline Pereira Moraes, Pierre-Alain Carrupt, Cecília M. A. de Oliveira, Amélia T. Henriques, Luiz Carlos Klein-Júnior, Eduardo Luis Konrath, and Lucilia Kato
- Subjects
Indoles ,Monoamine Oxidase Inhibitors ,Stereochemistry ,Hydantoin ,Cofactor ,Indole Alkaloids ,chemistry.chemical_compound ,Drug Discovery ,Cholinesterases ,Humans ,Monoamine Oxidase ,Butyrylcholinesterase ,Indole test ,chemistry.chemical_classification ,Molecular Structure ,biology ,Hydrogen bond ,Active site ,Neurodegenerative Diseases ,General Medicine ,Amino acid ,Enzyme ,chemistry ,biology.protein ,Cholinesterase Inhibitors ,Psychotria ,Central Nervous System Agents - Abstract
Indole alkaloids and synthetic indole derivatives are well known for their therapeutic importance. In fact, preclinical and clinical studies had already demonstrated several pharmacological activities for these compounds. Here, we overview the multifunctional potential of these molecules for the inhibition of enzymes related to neurodegenerative disease: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases A and B (MAO-A and MAO-B). A focus will be given on Psychotria L. genus, considering its reported central effects. Finally, three Psychotria alkaloids, namely desoxycordiofoline (61), bahienoside A (64) and bufotenine (65), along with the synthetic indole derivatives (5S)- 5-(1H-indol-3-ylmethyl)imidazolidine-2,4-dione (66), 5-(1H-indol-3-ylmethyl)-2-thioxoimidazolin-4-one (67), 5-(1Hindol- 3-ylmethyl)-3-methyl-2-thioxoimidazolidin-4-one (68), and methyl 2-(aminoN-(2-(4-methylcyclohex-3-enyl)propan- 2-yl)methanethioamino)-3-(1H-indol-3-yl)propanoate (69), were evaluated in vitro regarding their interactions with AChE, BChE, MAO-A and MAO-B. It was observed that 66 and 68 were able to inhibit MAO-A activity with IC 50 value of 8.23 and 0.07 μM. Molecular docking calculations were performed in order to understand the interactions between both ligands (66 and 68) and MAO-A. It was observed that the indole scaffold of both compounds bind into the MAO-A active site in the same orientation, establishing van der Waals contacts with lipophilic amino acids. Additionally, the hydantoin ring of 66 is able to interact by hydrogen bonds with two conserved water molecules in the MAO-A active site, while the methyl-thiohydantoin ring of 68 is within hydrogen bond distance from the hydrogen atom attached to the (N-5) of FAD cofactor. Taking together, our findings demonstrate that the indolyl-hydantoin and indolylmethyl-thiohydantoin rings might consists of good scaffolds for the development of new MAO-A inhibitors possessing neuroprotective properties.
- Published
- 2014
34. Antifungals and acetylcholinesterase inhibitors from the stem bark of Croton heliotropiifolius
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Jean-Luc Wolfender, Pierre-Alain Carrupt, Vanderlan da Silva Bolzani, Muriel Cuendet, Marçal de Queiroz Paulo, Quentin Favre-Godal, Laurence Marcourt, Maria Luiza Zeraik, Claudia A. Simões-Pires, Marcos Marçal Ferreira Queiroz, Guillaume Marti, and Emerson Ferreira Queiroz
- Subjects
ddc:615 ,Chromatography ,Indole alkaloid ,biology ,010405 organic chemistry ,Chemistry ,Euphorbiaceae ,Plant Science ,Fractionation ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Acetylcholinesterase ,High-performance liquid chromatography ,Thin-layer chromatography ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Candida albicans ,Agronomy and Crop Science ,Biotechnology - Abstract
The ethanolic extract of the stem bark of Croton heliotropiifolius Kunth (Euphorbiaceae) showed significant in vitro inhibition of acetylcholinesterase using a dilution spectrophotometric assay and antifungal activity against Candida albicans with a thin layer chromatography (TLC) bioautographic assay. In order to isolate the active compounds, bioassay-guided fractionation was undertaken using HPLC to localize the active compounds. Different zones of the HPLC-UV chromatogram were linked to acetylcholinesterase inhibition or to antifungal activities. In parallel to this HPLC-based activity profiling, HPLC-PDA-ESI-MS and HPLC-TOF-HRMS were used for the early identification of some of the compounds present. The targeted isolation of the active compounds was performed by medium pressure liquid chromatography (MPLC-UV) and further semi-preparative HPLC. Using this approach, nine compounds were isolated, one of them being a new indole alkaloid derivative. The structures of the isolated compounds were elucidated by spectroscopic methods including UV, NMR, MS and HRMS.
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- 2014
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35. Comparison of various silica-based monoliths for the analysis of large biomolecules†
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Karine Vuignier, Davy Guillarme, Jean-Luc Veuthey, Szabolcs Fekete, and Pierre-Alain Carrupt
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chemistry.chemical_classification ,geography ,geography.geographical_feature_category ,Chromatography ,Molecular mass ,Formic acid ,Biomolecule ,Filtration and Separation ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Phase (matter) ,Molecule ,Monolith ,Selectivity ,Protein adsorption - Abstract
In the present study, three types of silica-based monoliths, i.e. the first and second generations of commercial silica monolithic columns and a wide-pore prototype monolith were compared for the analysis of large biomolecules. These molecules possess molecular weights between 1 and 66 kDa. The gradient kinetic performance of the first-generation monolith was lower than that of the second generation, for large biomolecules (>14 kDa) but very close with smaller ones (1.3-5.8 kDa). In contrast, the wide-pore prototype column was particularly attractive with proteins larger than 19 kDa (higher peak capacity). Among these three columns, the selectivity and retention remained quite similar but a possible larger number of accessible and charged residual silanols was noticed on the wide-pore prototype material, which led to unpredicted small changes in selectivity and slightly broader peaks than expected. The peak shapes attained with the addition of 0.1% formic acid in the mobile phase remained acceptable for MS coupling, particularly for biomolecules of less than 6 kDa. It was found that one of the major issues with all of these silica-based monoliths is the possible poor recovery of large biomolecules (principally with monoclonal antibody fragments of more than 25 kDa).
- Published
- 2013
36. Methodologies to Assess Drug Permeation Through the Blood–Brain Barrier for Pharmaceutical Research
- Author
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Sophie Martel, Céline Passeleu-Le Bourdonnec, Jean Michel Scherrmann, and Pierre-Alain Carrupt
- Subjects
Drug ,media_common.quotation_subject ,In silico ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Pharmacology ,Biology ,Blood–brain barrier ,Permeability ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Pharmaceutical sciences ,media_common ,Drug discovery ,Organic Chemistry ,Biological Transport ,medicine.anatomical_structure ,Pharmaceutical Preparations ,Drug development ,Blood-Brain Barrier ,Molecular Medicine ,Biotechnology - Abstract
The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier.
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- 2013
37. A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors
- Author
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Carolina dos Santos Passos, Nathalie Deschamps, Pierre-Alain Carrupt, Alessandra Nurisso, Laura Goracci, Claudia A. Simões-Pires, Charlotte Petit, and Giuseppe Marco Randazzo
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0301 basic medicine ,Biology ,Histone Deacetylase 6 ,Hydroxamic Acids ,Article ,Histone H4 ,03 medical and health sciences ,Tubulin ,Neoplasms ,Humans ,Protein Isoforms ,Multidisciplinary ,Rational design ,Computational Biology ,Acetylation ,HDAC6 ,3. Good health ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Aggresome ,Biochemistry ,Drug development ,Blood-Brain Barrier ,biology.protein ,Histone deacetylase ,Protein Processing, Post-Translational ,Databases, Chemical - Abstract
The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays and its low cytotoxicity in vitro, suggested its potential for drug development.
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- 2016
38. Normal phase HPLC-based activity profiling of non-polar crude plant extracts – acetylcholinesterase inhibiting guttiferones from Montrouziera cauliflora as a case study
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Dang Bach Taï, Laurence Marcourt, Pascal Richomme, Samuel Bertrand, Pierre-Alain Carrupt, Anne Landreau, Jean-Luc Wolfender, Marc Litaudon, David Guilet, Claudia A. Simões-Pires, Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), Ecole de Pharmacie Genève Lausanne (EPGL), Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
- Subjects
Aché ,[SDV]Life Sciences [q-bio] ,Plant Science ,Fractionation ,01 natural sciences ,Biochemistry ,High-performance liquid chromatography ,Analytical Chemistry ,HPLC microfractionation ,chemistry.chemical_compound ,NP HPLC ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,Clusiaceae ,[CHIM]Chemical Sciences ,Montrouziera cauliflora ,ddc:615 ,Chromatography ,biology ,010405 organic chemistry ,Normal phase ,Guttiferone ,Organic Chemistry ,acetylcholinesterase ,biology.organism_classification ,Acetylcholinesterase ,language.human_language ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,language ,Tocotrienol - Abstract
International audience; The study describes bioactive compounds as inhibitors of acetylcholinesterase (AChE), from the stem bark extract of Montrouziera cauliflora, selected among 19 dichloromethane extracts from Clusiaceae species. Our work focused on the development of an original normal phase HPLC microfractionation strategy to rapidly assess highly active zones from this crude active non-polar plant extract. Two different microfraction collection methods were evaluated for the assessment of the AChE inhibition. Two guttiferones and a tocotrienol were directly isolated among five compounds identified off-line by NMR after upscaling the fractionation and their AChE inhibition was evaluated. The strengths and weaknesses of the two microfractionation collection methods for HPLC-AChE activity-based profiling are discussed.
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- 2016
39. Molecular dynamics of zinc-finger ubiquitin binding domains: a comparative study of histone deacetylase 6 and ubiquitin-specific protease 5
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Alessandra Nurisso, Carolina dos Santos Passos, Pierre-Alain Carrupt, and Claudia A. Simões-Pires
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0301 basic medicine ,Ubiquitin binding ,Molecular Dynamics Simulation ,Histone Deacetylase 6 ,01 natural sciences ,Molecular mechanics ,Histone Deacetylases ,03 medical and health sciences ,Molecular dynamics ,Ubiquitin ,Structural Biology ,0103 physical sciences ,Endopeptidases ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Molecular Biology ,Zinc finger ,010304 chemical physics ,biology ,Hydrogen Bonding ,Zinc Fingers ,General Medicine ,HDAC6 ,Alanine scanning ,030104 developmental biology ,Biochemistry ,biology.protein ,Biophysics ,Histone deacetylase ,Hydrophobic and Hydrophilic Interactions ,Protein Binding - Abstract
HDAC6 is a unique cytoplasmic histone deacetylase characterized by two deacetylase domains, and by a zinc-finger ubiquitin binding domain (ZnF-UBP) able to recognize ubiquitin (Ub). The latter has recently been demonstrated to be involved in the progression of neurodegenerative diseases and in mediating infection by the influenza A virus. Nowadays, understanding the dynamic and energetic features of HDAC6 ZnF-UBP-Ub recognition is considered as a crucial step for the conception of HDAC6 potential modulators. In this study, the atomic, solvent-related, and thermodynamic features behind HDAC6 ZnF-UBP-Ub recognition have been analyzed through molecular dynamics simulations. The behavior was then compared to the prototypical ZnF-UBP from ubiquitin-specific protease 5 (USP5) in order to spot relevant differences useful for selective drug design. Principal component analysis highlighted flapping motions of the L2A loop which were lowered down upon Ub binding in both systems. While polar and nonpolar interactions involving Ub G75 and G76 residues were also common features stabilizing both complexes, salt bridges showed a different pattern, more significant in HDAC6 ZnF-UBP-Ub, whose energetic contribution in USP5 ZnF-UBP-Ub was compensated by the presence of a more stable bridging water molecule. Whereas molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energies of binding were comparable for both systems, in agreement with experiments, computational alanine scanning and free energy decomposition data revealed that HDAC6 E1141 and D1178 are potential hotspots for the design of selective HDAC6 modulators.
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- 2016
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40. Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)
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Alban Bujard, Sylvian Cretton, Charlotte Petit, Joëlle Houriet, Jean-Luc Wolfender, Krystyna Skalicka-Woźniak, Philippe Christen, and Pierre-Alain Carrupt
- Subjects
Cell Membrane Permeability ,Bioavailability ,Ultraviolet Rays ,Angelica archangelica ,Synthetic membrane ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Intestinal absorption ,Analytical Chemistry ,Absorption ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,N vitro methods ,Drug Discovery ,Alkanes ,Medicinal plants ,Chromatography, High Pressure Liquid ,Pharmacology ,ddc:615 ,Natural products ,Chromatography ,Natural product ,Plants, Medicinal ,biology ,Traditional medicine ,Chemistry ,Plant Extracts ,Organic Chemistry ,Membranes, Artificial ,Permeation ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Medicinal extracts ,PAMPA ,Membrane ,Complementary and alternative medicine ,Intestinal Absorption ,Screening ,Molecular Medicine ,Passive intestinal absorption ,Waltheria indica ,0210 nano-technology - Abstract
At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay is one of the most frequently used in vitro models to predict transcellular passive absorption. While thousands of new chemical entities have been screened with the parallel artificial membrane permeability assay, in general, permeation properties of natural products have been scarcely evaluated. In this study, the parallel artificial membrane permeability assay through a hexadecane membrane was used to predict the passive intestinal absorption of a representative set of frequently occurring natural products. Since natural products are usually ingested for medicinal use as components of complex extracts in traditional herbal preparations or as phytopharmaceuticals, the applicability of such an assay to study the constituents directly in medicinal crude plant extracts was further investigated. Three representative crude plant extracts with different natural product compositions were chosen for this study. The first extract was composed of furanocoumarins (Angelica archangelica), the second extract included alkaloids (Waltheria indica), and the third extract contained flavonoid glycosides (Pueraria montana var. lobata). For each medicinal plant, the effective passive permeability values Pe (cm/s) of the main natural products of interest were rapidly calculated thanks to a generic ultrahigh-pressure liquid chromatography-UV detection method and because Pe calculations do not require knowing precisely the concentration of each natural product within the extracts. The original parallel artificial membrane permeability assay through a hexadecane membrane was found to keep its predictive power when applied to constituents directly in crude plant extracts provided that higher quantities of the extract were initially loaded in the assay in order to ensure suitable detection of the individual constituents of the extracts. Such an approach is thus valuable for the high-throughput, cost-effective, and early evaluation of passive intestinal absorption of active principles in medicinal plants. In phytochemical studies, obtaining effective passive permeability values of pharmacologically active natural products is important to predict if natural products showing interesting activities in vitro may have a chance to reach their target in vivo.
- Published
- 2016
41. Determination of alkane/water partition coefficients of polar compounds using hydrophilic interaction chromatography
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Sophie Martel, Pierre-Alain Carrupt, and Bruno Bard
- Subjects
Alkane ,chemistry.chemical_classification ,Acetonitriles ,Chromatography ,Chemistry ,Chemical polarity ,Hydrophilic interaction chromatography ,Organic Chemistry ,Analytical chemistry ,Water ,General Medicine ,Biochemistry ,Analytical Chemistry ,Partition coefficient ,chemistry.chemical_compound ,Membrane ,Alkanes ,Lipophilicity ,Linear Models ,Polar ,Organic Chemicals ,Acetonitrile ,Hydrophobic and Hydrophilic Interactions ,Chromatography, Liquid - Abstract
In this study, the retention factors (logk) of 44 polar neutral compounds were measured using hydrophilic interaction chromatography (HILIC). This retention parameter was compared with experimental logPalk obtained by a traditional method (shake-flask) or with the calculated logPalk for the most hydrophilic compounds. A good correlation was obtained between logk90 (measured with a mobile phase containing 90% acetonitrile) and logPalk. In contrast, no correlation was obtained between the retention factor and logPoct. This method could thus represent an advantageous alternative and reliable method to characterise the lipophilicity of polar compounds in an alkane/water system by chromatography, providing an important insight in (Q)SAR studies to predict drug permeation through numerous biorelevant membranes.
- Published
- 2012
42. Molecular Docking Using the Molecular Lipophilicity Potential as Hydrophobic Descriptor: Impact on GOLD Docking Performance
- Author
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Juan Bravo, Pierre-Alain Carrupt, Antoine Daina, and Alessandra Nurisso
- Subjects
Models, Molecular ,Protein cavities ,Binding Sites ,Ligand ,Chemistry ,General Chemical Engineering ,Proteins ,General Chemistry ,Library and Information Sciences ,Ligands ,Computer Science Applications ,Partition coefficient ,Crystallography ,Protein structure ,Searching the conformational space for docking ,Docking (molecular) ,Computational chemistry ,Drug Design ,Lipophilicity ,Humans ,Binding site ,Hydrophobic and Hydrophilic Interactions ,Software - Abstract
GOLD is a molecular docking software widely used in drug design. In the initial steps of docking, it creates a list of hydrophobic fitting points inside protein cavities that steer the positioning of ligand hydrophobic moieties. These points are generated based on the Lennard-Jones potential between a carbon probe and each atom of the residues delimitating the binding site. To thoroughly describe hydrophobic regions in protein pockets and properly guide ligand hydrophobic moieties toward favorable areas, an in-house tool, the MLP filter, was developed and herein applied. This strategy only retains GOLD hydrophobic fitting points that match the rigorous definition of hydrophobicity given by the molecular lipophilicity potential (MLP), a molecular interaction field that relies on an atomic fragmental system based on 1-octanol/water experimental partition coefficients (log P(oct)). MLP computations in the binding sites of crystallographic protein structures revealed that a significant number of points considered hydrophobic by GOLD were actually polar according to the MLP definition of hydrophobicity. To examine the impact of this new tool, ligand-protein complexes from the Astex Diverse Set and the PDB bind core database were redocked with and without the use of the MLP filter. Reliable docking results were obtained by using the MLP filter that increased the quality of docking in nonpolar cavities and outperformed the standard GOLD docking approach.
- Published
- 2012
43. Synthesis physicochemical profile and PAMPA study of new NO-donor edaravone co-drugs
- Author
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Sophie Martel, Barbara Rolando, Pierre-Alain Carrupt, Marta Giorgis, Claudio De Nardi, Konstantin Chegaev, Roberta Fruttero, Andrea Filieri, Loretta Lazzarato, and Alberto Gasco
- Subjects
Antioxidant ,Stereochemistry ,Vasodilator Agents ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,In vitro permeability profile ,Biochemistry ,Permeability ,No donors ,Gastrointestinal absorption ,chemistry.chemical_compound ,Drug Stability ,Nitrate ,Edaravone ,Nitrooxy-acyl derivatives of edaravone ,Co-drugs ,Lipophilicity profile ,Drug Discovery ,medicine ,Animals ,Humans ,Organic chemistry ,Nitric Oxide Donors ,Nitrite ,Molecular Biology ,Nitrites ,ddc:615 ,Nitrates ,Organic Chemistry ,Rats ,chemistry ,Lipophilicity ,Molecular Medicine ,Antipyrine - Abstract
A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO x ) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.
- Published
- 2012
44. Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization
- Author
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Antoine Daina, Liliana Sintra Grilo, Pierre-Alain Carrupt, and Hugues Abriel
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Molecular model ,hERG ,Action Potentials ,Molecular Dynamics Simulation ,Pharmacology ,Transfection ,Molecular mechanics ,03 medical and health sciences ,0302 clinical medicine ,Anti-Allergic Agents ,Drug Discovery ,Potassium Channel Blockers ,medicine ,Humans ,cardiovascular diseases ,Anesthetics, Local ,030304 developmental biology ,Bupivacaine ,0303 health sciences ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Arrhythmias, Cardiac ,Heart ,Stereoisomerism ,Cardiac action potential ,Potassium channel blocker ,General Medicine ,Ether-A-Go-Go Potassium Channels ,Recombinant Proteins ,Potassium channel ,3. Good health ,HEK293 Cells ,Docking (molecular) ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Thermodynamics ,Terfenadine ,Plasmids ,Protein Binding ,medicine.drug - Abstract
The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.
- Published
- 2011
45. Lipophilicity Determination of Highly Lipophilic Compounds by Liquid Chromatography
- Author
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Amandine Guillot, Jean-Luc Veuthey, Yveline Henchoz, Davy Guillarme, Cyril Moccand, Pierre-Alain Carrupt, and Sophie Martel
- Subjects
Liquid chromatography ,Analytical chemistry ,Bioengineering ,Buffers ,Biochemistry ,High-performance liquid chromatography ,chemistry.chemical_compound ,Amide ,Lipophilicity ,Pharmacokinetics ,Solubility ,Hplc method ,Molecular Biology ,Chromatography, High Pressure Liquid ,ddc:615 ,Lipophilic determination ,Chromatography ,Elution ,Chemistry ,Methanol ,General Chemistry ,General Medicine ,Hydrogen-Ion Concentration ,Lipids ,Partition coefficient ,Pharmaceutical Preparations ,Stationary phase ,Solvents ,Molecular Medicine ,Indicators and Reagents ,Algorithms - Abstract
Different experimental strategies using short columns in both conventional liquid chromatography (HPLC) and ultra-high pressure liquid chromatography (UHPLC) were evaluated to allow, for the first time with these techniques, the lipophilicity determination of compounds with log P>5. Various organic modifiers, stationary phases, and elution modes were tested on 14 rigid compounds with a CLogP between 5 and 8, and 38 compounds with log P(oct) from 0 to 5. The best results in HPLC were obtained with the 20-mm Discovery RP Amide C16 stationary phase in isocratic mode using MeOH as organic modifier. To improve analysis time, the UHPLC approach was then evaluated. Consequently, a generic method was developed with a 30-mm Acquity BEH Shield RP18 column in gradient mode using MeOH as organic modifier, allowing a fourfold gain of time compared to the HPLC method, for the highly lipophilic compounds tested. Finally, the most rapid and accurate results were obtained with a 10-mm Hypersil GOLD Javelin HTS stationary phase in UHPLC, enabling an eightfold gain of time compared to the HPLC method.
- Published
- 2009
46. In SilicoTools andIn VitroHTS Approaches to Determine Lipophilicity During the Drug Discovery Process
- Author
-
Pierre-Alain Carrupt, Vincent Gasparik, and Sophie Martel
- Subjects
Drug discovery ,Chemistry ,In silico ,Lipophilicity ,Computational biology ,Data mining ,computer.software_genre ,computer - Published
- 2009
47. UPLC–TOF-MS for plant metabolomics: A sequential approach for wound marker analysis in Arabidopsis thaliana
- Author
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Julien Boccard, Jean-Luc Wolfender, Pierre-Alain Carrupt, Davy Guillarme, Edward E. Farmer, Elia Grata, Gaétan Glauser, and Serge Rudaz
- Subjects
Metabolite ,Clinical Biochemistry ,Arabidopsis ,Marker analysis ,Arabidopsis/metabolism ,Mass spectrometry ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,chemistry.chemical_compound ,Metabolomics ,Arabidopsis thaliana ,Plants/metabolism ,Mass Spectrometry/methods ,Chromatography, High Pressure Liquid ,Unsaturated fatty acid ,Plant Diseases ,ddc:615 ,Principal Component Analysis ,Chromatography ,biology ,Computational Biology ,Cell Biology ,General Medicine ,Computational Biology/methods ,Plants ,biology.organism_classification ,Uplc tof ms ,chemistry ,Stress induction ,Chromatography, High Pressure Liquid/methods - Abstract
The model plant Arabidopsis thaliana was studied for the search of new metabolites involved in wound signalling. Diverse LC approaches were considered in terms of efficiency and analysis time and a 7-min gradient on a UPLC-TOF-MS system with a short column was chosen for metabolite fingerprinting. This screening step was designed to allow the comparison of a high number of samples over a wide range of time points after stress induction in positive and negative ionisation modes. Thanks to data treatment, clear discrimination was obtained, providing lists of potential stress-induced ions. In a second step, the fingerprinting conditions were transferred to longer column, providing a higher peak capacity able to demonstrate the presence of isomers among the highlighted compounds.
- Published
- 2008
48. In vitro screening assays to identify natural or synthetic acetylcholinesterase inhibitors: Thin layer chromatography versus microplate methods
- Author
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Pierre-Alain Carrupt, Kurt Hostettmann, Marianne Reist, Aurélie Urbain, Aline Borloz, Andrew Marston, and Saviana Di Giovanni
- Subjects
Diazonium Compounds/chemistry ,Drug Evaluation, Preclinical ,Silica Gel ,Pharmaceutical Science ,Dithionitrobenzoic Acid ,Naphthols ,Catalysis ,chemistry.chemical_compound ,Dithionitrobenzoic Acid/chemistry ,Silicon Dioxide/chemistry ,Acetylcholinesterase/chemistry/metabolism ,Animals ,Dimethyl Sulfoxide ,Plate assay ,chemistry.chemical_classification ,ddc:615 ,Dimethyl Sulfoxide/chemistry ,Chromatography ,Molecular Structure ,Naphthols/chemistry ,Silica gel ,Electrophorus/metabolism ,Diazonium Compounds ,Silicon Dioxide ,Cholinesterase Inhibitors/analysis/chemistry/isolation & purification ,Acetylcholinesterase ,Thin-layer chromatography ,In vitro ,Fast blue B salt ,Kinetics ,Enzyme ,chemistry ,Reagent ,Electrophorus ,Cholinesterase Inhibitors ,Chromatography, Thin Layer ,Drug Evaluation, Preclinical/methods ,Chromatography, Thin Layer/methods - Abstract
Acetylcholinesterase inhibitors (AChEI) are currently still the best available pharmacotherapy for Alzheimer patients. Successful screening for new AChEI relies on effective and fast assays. Two colorimetric screening assays frequently used to search for new AChEI, namely a thin layer chromatography (TLC) assay with Fast Blue B salt as reagent and a 96-well plate assay based on Ellman's method, were compared. For the majority (83%) of the 138 test compounds of natural and synthetic origin, the results obtained with the two assays converged and both screening assays were considered suitable for the generation of new hits. Fifteen percent of investigated compounds were classified as active with the microplate assay but were shown to be inactive by TLC and about 2% were measured active by TLC but showed to be inactive with the microplate assay. These divergences were not due to the main differences between the experimental protocols of the two screening assays, namely the different colorimetric methods and pre-incubation of test compounds with acetylcholinesterase (AChE). They might be explained by the interaction of either AChE or test compounds with the silica of the TLC plates, resulting in an altered affinity of the enzyme for the compounds.
- Published
- 2008
49. Chromatographic Approaches for Measuring Log P
- Author
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Pierre-Alain Carrupt, Sophie Martel, Serge Rudaz, Yveline Henchoz, Davy Guillarme, Jean-Luc Veuthey, and Alexandra Galland
- Subjects
Partition coefficient ,ddc:615 ,Chromatography ,Chemistry ,Lipophilicity - Published
- 2007
50. Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases
- Author
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Carolina dos Santos Passos, Cosimo Altomare, Estefanía Méndez-Álvarez, Alessandra Nurisso, Roberta Farina, Leonardo Pisani, Pierre-Alain Carrupt, Angelo Carotti, Orazio Nicolotti, Giovanni Muncipinto, Marco Catto, Nunzio Denora, Ramón Soto-Otero, and Domenico Gadaleta
- Subjects
Aminocoumarins ,Monoamine Oxidase Inhibitors ,Monoamine oxidase ,Protein Conformation ,Neuroprotection ,Permeability ,Madin Darby Canine Kidney Cells ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Dogs ,Coumarins ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Cholinesterases ,Humans ,Cytotoxicity ,Monoamine Oxidase ,Chemistry ,Neurotoxicity ,medicine.disease ,Rats ,Molecular Docking Simulation ,Monoamine neurotransmitter ,Biochemistry ,Blood-Brain Barrier ,Drug Design ,Molecular Medicine ,Monoamine oxidase B ,Cholinesterase Inhibitors - Abstract
The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
- Published
- 2015
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