Search

Your search keyword '"Lionel Colliandre"' showing total 17 results
Start Over Author "Lionel Colliandre"
17 results on '"Lionel Colliandre"'

1. AI4DR: Development and implementation of an annotation system for high-throughput dose-response experiments

Author

Marc Bianciotto, Lionel Colliandre, Kun Mi, Isabelle Schreiber, Cécile Delorme, Stéphanie Vougier, and Hervé Minoux

Subjects
Dose-response curve, Artificial intelligence, Annotation system, High throughput screening, Science (General), Q1-390
Abstract

One of the common strategies to identify novel chemical matter in drug discovery consists in performing a High Throughput Screening (HTS). However, the large amount of data generated at the dose-response (DR) step of an HTS campaign requires a careful analysis to detect artifacts and correct erroneous datapoints before validating the experiments. This step which requires to review each DR experiment can be time consuming and prone to human errors or inconsistencies. AI4DR is a system that has been developed for the classification of DR curves based on a Convolutional Neural Network (CNN) acting on normalized images of the DR curves. AI4DR allows the annotation in minutes of thousands of curves among 14 categories to help the High Throughput Screening biologists in their analyses. Several categories are associated with active and inactive compounds, other categories correspond to features of interest such as the presence of noise, a weaker effect at high doses, or a suspiciously weak or strong slope at the inflexion point of the DR curves of actives. The classifier has been trained on an algorithmically generated dataset curated and refined by experts, tested using real screening campaigns and improved using thousands of annotations by experts. The solution is deployed using a MLFlow model server interfaced with the Genedata Screener data analysis software used by the end users. AI4DR improves the consistency, the robustness, and the speed of HTS data analysis as well as reducing the human effort to identify faster new medicines for patients.

Published
2023
Full Text
View/download PDF

2. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

Author

Abdelhakim Ahmed-Belkacem, Lionel Colliandre, Nazim Ahnou, Quentin Nevers, Muriel Gelin, Yannick Bessin, Rozenn Brillet, Olivier Cala, Dominique Douguet, William Bourguet, Isabelle Krimm, Jean-Michel Pawlotsky, and Jean- François Guichou

Subjects
Science
Abstract

Cyclophilins play a key role in the life cycle of many viruses and represent important drug targets for broad-spectrum antiviral therapies. Here, the authors use fragment-based drug discovery to develop non-peptidic inhibitors of human cyclophilins with high activity against replication of a number of viral families.

Published
2016
Full Text
View/download PDF

7. Découverte d’une nouvelle famille de petites molécules non-peptidiques inhibitrices des Cyclophilines ayant une probable activité antivirale

Author

Olivier Cala, Abdelhakim Ahmed-Belkacem, Lionel Colliandre, Nazim Ahnou, Quentin Nevers, Muriel Gelin, Yannick Bessin, Rozenn Brillet, Dominique Douguet, William Bourguet, Isabelle Krimm, Jean -Michel Pawlotsky, Jean-François Guichou, ISA - Méthodes et criblage RMN pour les molécules bioactives, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement d'études de résonance magnétique, Bussy, Agnès, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[CHIM] Chemical Sciences, [CHIM]Chemical Sciences
Abstract

http://thcgerm.free.fr/spip.php?article123; National audience

Published
2017

8. Identification of New Nonsteroidal RORα Ligands; Related Structure–Activity Relationships and Docking Studies

Author

Jean-François Delhomel, Stéphane Helleboid, Matthieu Daillet, Sébastien Daix, Robert Walczak, Mathieu Dubernet, Lionel Colliandre, Luc Morin-Allory, Sylvain Routier, Christophe Berini, Lucie Maingot, Nicolas Duguet, and Marilyne Bourotte

Subjects
chemistry.chemical_compound, Nonsteroidal, Chemistry, Hydrogen bond, Stereochemistry, Docking (molecular), Organic Chemistry, Drug Discovery, Benzyl group, Moiety, Bioinformatics, Biochemistry
Abstract

A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.

Published
2013
Full Text
View/download PDF

9. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

Author

Lionel Colliandre, Abdelhakim Ahmed-Belkacem, Dominique Douguet, Olivier Cala, William Bourguet, Quentin Nevers, Muriel Gelin, Isabelle Krimm, Rozenn Brillet, Yannick Bessin, Nazim Ahnou, Jean-Michel Pawlotsky, Jean-François Guichou, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), ISA - Méthodes et criblage RMN pour les molécules bioactives, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, the Fonds Europeen de Developpement Economique et Regional (FEDER) Number 48748, the Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) and the Fondation pour la Recherche Medicale (FRM)., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Bussy, Agnès, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, CYCLOSPORINE-A, Hepatitis C virus, Science, General Physics and Astronomy, Isomerase, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, MECHANISMS, T-CELL-ACTIVATION, 03 medical and health sciences, DESIGN, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, medicine, polycyclic compounds, Peptide bond, Cyclophilin, Alisporivir, Multidisciplinary, Drug discovery, General Chemistry, ALISPORIVIR, Antivirals, Small molecule, Virology, 3. Good health, APOPTOSIS, GENOTYPE, DRUG DISCOVERY, MITOCHONDRIAL PERMEABILITY TRANSITION, 030104 developmental biology, Biochemistry, REPLICATION, Nucleic acid, Structure-based drug design, Pathogens
Abstract

Cyclophilins are peptidyl-prolyl cis/trans isomerases (PPIase) that catalyse the interconversion of the peptide bond at proline residues. Several cyclophilins play a pivotal role in the life cycle of a number of viruses. The existing cyclophilin inhibitors, all derived from cyclosporine A or sanglifehrin A, have disadvantages, including their size, potential for side effects unrelated to cyclophilin inhibition and drug–drug interactions, unclear antiviral spectrum and manufacturing issues. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule cyclophilin inhibitors with potent in vitro PPIase inhibitory activity and antiviral activity against hepatitis C virus, human immunodeficiency virus and coronaviruses. This family of compounds has the potential for broad-spectrum, high-barrier-to-resistance treatment of viral infections., Cyclophilins play a key role in the life cycle of many viruses and represent important drug targets for broad-spectrum antiviral therapies. Here, the authors use fragment-based drug discovery to develop non-peptidic inhibitors of human cyclophilins with high activity against replication of a number of viral families.

Published
2015
Full Text
View/download PDF

10. Design, Synthesis, and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/mTOR Dual Inhibitors

Author

Pascal Bonnet, Christiane Guillouzo, Hélène Bénédetti, Anne Corlu, Sylvain Routier, Marie-Lise Jourdan, Thibault Saurat, Gérald Guillaumet, Marie-Ludivine de Tauzia, Pascale Rio, Lionel Colliandre, Mohamed Akssira, Stéphane Bourg, Frédéric Buron, Nuno Rodrigues, Pauline Berthier, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centro de Estudos Geograficos, IGOT, Universidade de Lisboa (ULISBOA), Centre de biophysique moléculaire (CBM), Laboratoire de Chimie Physique & de Chimie Bioorganique, URAC 22 (LCPCB), Faculte des sciences et Techniques Mohammedia [Casablanca] (FSTM), Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Centre de Formation et de Recherche sur les Environnements Méditérranéens (CEFREM), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours

Subjects
Cell cycle checkpoint, Pyridines, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Apoptosis, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, Structure-Activity Relationship, In vivo, Cell Line, Tumor, Drug Discovery, Humans, Computer Simulation, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, 010405 organic chemistry, Chemistry, Kinase, TOR Serine-Threonine Kinases, G1 Phase, Biological activity, Fibroblasts, 0104 chemical sciences, Isoenzymes, Molecular Docking Simulation, Pyrimidines, Biochemistry, Docking (molecular), Cell culture, Drug Design, Cancer cell, Molecular Medicine, Drug Screening Assays, Antitumor
Abstract

International audience; The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments.

Published
2014
Full Text
View/download PDF

11. Visual Characterization and Diversity Quantification of Chemical Libraries: 2. Analysis and Selection of Size-Independent, Subspace-Specific Diversity Indices

Author

Vincent Le Guilloux, Lionel Colliandre, Stéphane Bourg, Luc Morin-Allory, Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
General Chemical Engineering, Drug Evaluation, Preclinical, MOLECULAR DIVERSITY, Context (language use), Library and Information Sciences, Biology, DATABASES, computer.software_genre, 01 natural sciences, Set (abstract data type), Small Molecule Libraries, 03 medical and health sciences, DESIGN, MESH: Small Molecule Libraries, Methods, SPACE, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ALGORITHM, MESH: Methods, Selection (genetic algorithm), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, General Chemistry, Function (mathematics), Partition (database), Linear subspace, 0104 chemical sciences, Computer Science Applications, DRUG DISCOVERY, 010404 medicinal & biomolecular chemistry, LEAD DISCOVERY, Outlier, VISUALIZATION, MESH: Drug Evaluation, Preclinical, Data mining, computer, Subspace topology, [CHIM.CHEM]Chemical Sciences/Cheminformatics, COMBINATORIAL LIBRARY
Abstract

International audience; High Throughput Screening (HTS) is a standard technique widely used to find hit compounds in drug discovery projects. The high costs associated with such experiments have highlighted the need to carefully design screening libraries in order to avoid wasting resources. Molecular diversity is an established concept that has been used to this end for many years. In this article, a new approach to quantify the molecular diversity of screening libraries is presented. The approach is based on the Delimited Reference Chemical Subspace (DRCS) methodology, a new method that can be used to delimit the densest subspace spanned by a reference library in a reduced 2D continuous space. A total of 22 diversity indices were implemented or adapted to this methodology, which is used here to remove outliers and obtain a relevant cell-based partition of the subspace. The behavior of these indices was assessed and compared in various extreme situations and with respect to a set of theoretical rules that a diversity function should satisfy when libraries of different sizes have to be compared. Some gold standard indices are found inappropriate in such a context, while none of the tested indices behave perfectly in all cases. Five DRCS-based indices accounting for different aspects of diversity were finally selected, and a simple framework is proposed to use them effectively. Various libraries have been profiled with respect to more specific subspaces, which further illustrate the interest of the method.

Published
2012
Full Text
View/download PDF

12. e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design

Author

Jean-François Guichou, Lionel Colliandre, Emilie Pihan, Dominique Douguet, Douguet, dominique, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Nice Sophia Antipolis (... - 2019) (UNS)

Subjects
Statistics and Probability, Drug, Databases, Factual, Computer science, media_common.quotation_subject, In silico, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, World Wide Web, Cyclophilins, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, [CHIM.CHEM] Chemical Sciences/Cheminformatics, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Internet, 0303 health sciences, Drug discovery, Drug Repositioning, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Computer Science Applications, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Computational Mathematics, Drug repositioning, Models, Chemical, Pharmaceutical Preparations, Computational Theory and Mathematics, Drug Design, 030220 oncology & carcinogenesis, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

Motivation: In the drug discovery field, new uses for old drugs, selective optimization of side activities and fragment-based drug design (FBDD) have proved to be successful alternatives to high-throughput screening. e-Drug3D is a database of 3D chemical structures of drugs that provides several collections of ready-to-screen SD files of drugs and commercial drug fragments. They are natural inputs in studies dedicated to drug repurposing and FBDD. Availability: e-Drug3D collections are freely available at http://chemoinfo.ipmc.cnrs.fr/e-drug3d.html either for download or for direct in silico web-based screenings. Contact: douguet@ipmc.cnrs.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Published
2012
Full Text
View/download PDF

13. Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents

Author

Olivier Lozach, Laurent Meijer, Valérie Bénéteau, Krzysztof Lewiński, Stéphane Bourg, Sylvain Routier, Paméla Kassis, Christiane Guillouzo, Jean-Yves Mérour, Lionel Colliandre, Joanna Brzeszcz, Rémi Le Guével, Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Faculty of Chemistry, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ManRos Therapeutics, Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Indoles, Molecular model, Pyridines, CDK, Molecular Conformation, Chemistry Techniques, Synthetic, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, GSK3, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Drug Discovery, MESH: Protein Kinase Inhibitors, Microwaves, ComputingMilieux_MISCELLANEOUS, MESH: Indoles, 0303 health sciences, biology, General Medicine, Pyrazines, MESH: Pyrazines, pyrazine, cytotoxicity, Selectivity, MESH: Palladium, Palladium, MESH: Models, Molecular, pyridine, MESH: Cell Line, Tumor, Pyrazine, Stereochemistry, Antineoplastic Agents, MESH: Microwaves, Catalysis, 03 medical and health sciences, Structure-Activity Relationship, Cyclin-dependent kinase, Cell Line, Tumor, Pyridine, Humans, Protein Kinase Inhibitors, MESH: Protein Kinases, 030304 developmental biology, Pharmacology, Indole test, MESH: Molecular Conformation, MESH: Humans, molecular modeling, 010405 organic chemistry, Organic Chemistry, MESH: Pyridines, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DYRK1A, MESH: Catalysis, 0104 chemical sciences, Stille reaction, indole, chemistry, Docking (molecular), biology.protein, MESH: Antineoplastic Agents, MESH: Chemistry Techniques, Synthetic, Protein Kinases
Abstract

International audience; We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 μM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.

Published
2011
Full Text
View/download PDF

14. Visual Characterization and Diversity Quantification of Chemical Libraries: 1. Creation of Delimited Reference Chemical Subspaces

Author

Stéphane Bourg, Lionel Colliandre, Guillaume Guenegou, Vincent Le Guilloux, Luc Morin-Allory, Julie Dubois-Chevalier, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique Fondamentale d'Orléans (LIFO), Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges, Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Ecole Nationale Supérieure d'Ingénieurs de Bourges-Université d'Orléans (UO)

Subjects
Databases, Factual, Computer science, General Chemical Engineering, Chemistry, Pharmaceutical, MOLECULAR DESCRIPTORS, Space (commercial competition), MESH: Drug Design, computer.software_genre, 01 natural sciences, MESH: Structure-Activity Relationship, COMBINATORIAL LIBRARIES, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Principal Component Analysis, Molecular Structure, Linear subspace, Computer Science Applications, DEVELOPMENT KIT CDK, Data mining, SOURCE JAVA LIBRARY, Algorithms, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Matching (statistics), MEDICINAL CHEMISTRY SPACE, MESH: High-Throughput Screening Assays, MESH: Molecular Structure, Nanotechnology, MESH: Algorithms, Library and Information Sciences, Set (abstract data type), Small Molecule Libraries, 03 medical and health sciences, MESH: Chemistry, Pharmaceutical, Structure-Activity Relationship, MESH: Small Molecule Libraries, Molecular descriptor, Humans, SCREENING LIBRARIES, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, COMPOUND DATABASES, 030304 developmental biology, MESH: Principal Component Analysis, MESH: Humans, Models, Statistical, General Chemistry, MESH: Databases, Factual, Chemical space, 0104 chemical sciences, High-Throughput Screening Assays, DRUG DISCOVERY, 010404 medicinal & biomolecular chemistry, LEAD DISCOVERY, Drug Design, Key (cryptography), DIFFERENTIAL SHANNON ENTROPY, Robust principal component analysis, computer, MESH: Models, Statistical
Abstract

International audience; High-throughput screening (HTS) is a well-established technology which can test up to several million compounds in a few weeks. Despite these appealing capabilities, available resources and high costs may limit the number of molecules screened, making diversity analysis a method of choice to design and prioritize screening libraries. With a constantly increasing number of molecules available for screening, chemical space has become a key concept for visualizing, analyzing, and comparing chemical libraries. In this first article, we present a new method to build delimited reference chemical subspaces (DRCS). A set of 16 million screening compounds from 73 chemical providers has been gathered, resulting in a database of 6.63 million standardized and unique molecules. These molecules have been used to create three DRCS using three different sets of chemical descriptors. A robust principal component analysis model for each space has been obtained, whereby molecules are projected in a reduced two-dimensional viewable space. The specificity of our approach is that each reduced space has been delimited by a representative contour encompassing a very large proportion of molecules and reflecting its overall shape. The methodology is illustrated by mapping and comparing various chemical libraries. Several tools used in these studies are made freely available, thus enabling any user to compute DRCS matching specific requirements.

Published
2011
Full Text
View/download PDF

15. Synthesis and biological evaluation of 2,3-bis(het)aryl-4-azaindole derivatives as protein kinase inhibitors

Author

Frederic Pin, Lionel Colliandre, Rémy Le Guével, Françoise Schoentgen, Christiane Guillouzo, Sylvain Routier, Stéphane Bourg, Fabienne Saab, Frédéric Buron, Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Physique et Chimie du Vivant (PCV), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Génétique fonctionnelle, agronomie et santé (GFAS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Chimie Organique et Macromoléculaire (URCOM), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Interactions Cellulaires et Moléculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR98-Centre National de la Recherche Scientifique (CNRS), and Technologie Servier

Subjects
DYRK1A, Stereochemistry, [SDV]Life Sciences [q-bio], Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, PATHWAY, chemistry.chemical_compound, DESIGN, GSK-3, Drug Discovery, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase A, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, Kinase, Aryl, Organic Chemistry, RAF INHIBITORS, INTERNAL ALKYNES, GLYCOGEN-SYNTHASE KINASE-3, AZAINDOLES, MAP KINASE, 0104 chemical sciences, chemistry, Docking (molecular), 7-AZAINDOLES, Mitogen-activated protein kinase, biology.protein, PALLADIUM-CATALYZED HETEROANNULATION, Molecular Medicine, GROWTH, Selectivity
Abstract

International audience; The synthesis of several novel 4-azaindoles was carried out by novel Fischer reaction which offers as a main advantage, the synthesis of the bisfunctionalized 4-azaindolic building block in one step. The final compounds were evaluated on a panel of 5 kinases in order to evaluate their selectivity and on 7 cancer cell lines to determine their cytotoxic effects. RAF-1 and DYRK1A inhibitions were found, docking studies explain fully the results.

Published
2011
Full Text
View/download PDF

16. Inhibition of 7,8-diaminopelargonic acid aminotransferase from Mycobacterium tuberculosis by chiral and achiral anologs of its substrate: biological implications

Author

Lionel Colliandre, Olivier Ploux, Stéphane Mann, and Gilles Labesse

Subjects
Stereochemistry, Antitubercular Agents, Biotin, 01 natural sciences, Biochemistry, Cofactor, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, Escherichia coli, Amino Acids, Enzyme Inhibitors, Enantiomeric excess, Racemization, Transaminases, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Enantioselective synthesis, Amino Acids, Diamino, General Medicine, Mycobacterium tuberculosis, 3. Good health, 0104 chemical sciences, Enantiopure drug, biology.protein, Amine gas treating, Pyridoxamine, Acyltransferases, Cysteine
Abstract

7,8-Diaminopelargonic acid aminotransferase (DAPA AT), a potential drug target in Mycobacterium tuberculosis , transforms 8-amino-7-oxononanoic acid (KAPA) into DAPA. We have designed an analytical method to measure the enantiomeric excess of KAPA, based on the derivatization of its amine function, by ortho -phtalaldehyde and N -acetyl- l -cysteine, followed by high pressure liquid chromatography separation. Using this methodology and enantiopure samples of KAPA it appeared that racemization of KAPA occurs rapidly (half-lives from 1 to 8 h) not only in 4 M HCl but more importantly in the usual pH range, from 7 to 9. Furthermore, we showed that racemic KAPA, and not enantiopure KAPA, was used in all previous studies. The only valid enantioselective synthesis of KAPA is that reported by Lucet et al. (1996) Tetrahedron: Asymmetry 7, 985–988. KAPA is produced as a pure ( S )-enantiomer by KAPA synthase and by microbial production and DAPA AT only uses ( S )-KAPA as substrate. However, ( R )-KAPA is an inhibitor of this enzyme. It binds to the pyridoxal 5′-phosphate form ( K i1 = 5.9 ± 0.2 μM) and to the pyridoxamine 5′-phosphate form ( K i2 = 1.7 ± 0.2 μM) of M. tuberculosis DAPA AT. Molecular modeling showed that ( R )-KAPA forms specific hydrogen bonds with T309 and the phosphate group of the cofactor of DAPA AT. Desmethyl-KAPA (8-amino-7-oxooctanoic acid), an achiral analog of KAPA, is also a potent inhibitor of M. tuberculosis DAPA AT. This molecule binds to the enzyme in a similar way than ( R )-KAPA with the following constants: K i1 = 4.2 ± 0.2 μM, and K i2 = 0.9 ± 0.2 μM. These findings pave the way to the design of new antimycobacterial drugs.

Published
2009

Catalog

Books, media, physical & digital resources
See catalog results