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1. A refined picture of the native amine dehydrogenase family revealed by extensive biodiversity screening

Author

Eddy Elisée, Laurine Ducrot, Raphaël Méheust, Karine Bastard, Aurélie Fossey-Jouenne, Gideon Grogan, Eric Pelletier, Jean-Louis Petit, Mark Stam, Véronique de Berardinis, Anne Zaparucha, David Vallenet, and Carine Vergne-Vaxelaire

Subjects
Science
Abstract

Abstract Native amine dehydrogenases offer sustainable access to chiral amines, so the search for scaffolds capable of converting more diverse carbonyl compounds is required to reach the full potential of this alternative to conventional synthetic reductive aminations. Here we report a multidisciplinary strategy combining bioinformatics, chemoinformatics and biocatalysis to extensively screen billions of sequences in silico and to efficiently find native amine dehydrogenases features using computational approaches. In this way, we achieve a comprehensive overview of the initial native amine dehydrogenase family, extending it from 2,011 to 17,959 sequences, and identify native amine dehydrogenases with non-reported substrate spectra, including hindered carbonyls and ethyl ketones, and accepting methylamine and cyclopropylamine as amine donor. We also present preliminary model-based structural information to inform the design of potential (R)-selective amine dehydrogenases, as native amine dehydrogenases are mostly (S)-selective. This integrated strategy paves the way for expanding the resource of other enzyme families and in highlighting enzymes with original features.

Published
2024
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2. Native amine dehydrogenases can catalyze the direct reduction of carbonyl compounds to alcohols in the absence of ammonia

Author

Aurélie Fossey-Jouenne, Laurine Ducrot, Ewald P. J. Jongkind, Eddy Elisée, Anne Zaparucha, Gideon Grogan, Caroline E. Paul, and Carine Vergne-Vaxelaire

Subjects
amine dehydrogenases, ketoreduction, reductive amination, alcohol, docking, Chemistry, QD1-999
Abstract

Native amine dehydrogenases (nat-AmDHs) catalyze the (S)-stereoselective reductive amination of various ketones and aldehydes in the presence of high concentrations of ammonia. Based on the structure of CfusAmDH from Cystobacter fuscus complexed with Nicotinamide adenine dinucleotide phosphate (NADP+) and cyclohexylamine, we previously hypothesized a mechanism involving the attack at the electrophilic carbon of the carbonyl by ammonia followed by delivery of the hydride from the reduced nicotinamide cofactor on the re-face of the prochiral ketone. The direct reduction of carbonyl substrates into the corresponding alcohols requires a similar active site architecture and was previously reported as a minor side reaction of some native amine dehydrogenases and variants. Here we describe the ketoreductase (KRED) activity of a set of native amine dehydrogenases and variants, which proved to be significant in the absence of ammonia in the reaction medium but negligible in its presence. Conducting this study on a large set of substrates revealed the heterogeneity of this secondary ketoreductase activity, which was dependent upon the enzyme/substrate pairs considered. In silico docking experiments permitted the identification of some relationships between ketoreductase activity and the structural features of the enzymes. Kinetic studies of MsmeAmDH highlighted the superior performance of this native amine dehydrogenases as a ketoreductase but also its very low activity towards the reverse reaction of alcohol oxidation.

Published
2023
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7. Expanding the Substrate Scope of Native Amine Dehydrogenases through In Silico Structural Exploration and Targeted Protein Engineering

Author

Laurine Ducrot, Megan Bennett, Gwenaëlle André‐Leroux, Eddy Elisée, Sacha Marynberg, Aurélie Fossey‐Jouenne, Anne Zaparucha, Gideon Grogan, Carine Vergne‐Vaxelaire, Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Structural Biology Laboratory, Department of Chemistry, University of York, Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Region Ile-de-France, Diamond Light Source Didcot UKmx24948, and ANR-19-CE07-0007,MODAMDH,Découverte et étude d'amine dehydrogénases par approche in silico(2019)

Subjects
Inorganic Chemistry, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, native amine dehydrogenases, Organic Chemistry, protein engineering, [CHIM.CATA]Chemical Sciences/Catalysis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Physical and Theoretical Chemistry, structural biodiversity, reductive amination, molecular dynamics, Catalysis
Abstract

International audience; Native Amine Dehydrogenases (nat-AmDHs) are NAD(P)H-enzymes performing reductive amination, mainly active towards small aliphatic aldehydes and cyclic ketones, due to active site volumes limited by the presence of several bulky amino acids. Herein, inspired by the diversity of residues at these positions among the family, we report the implementation of mutations F140A and W145A in CfusAmDH and their transposition in nine other members. Moderate to high conversions were obtained with substrates not accepted by the native enzymes, notably n-alkylaldehydes (44.6% - 99.5% for hexanal to nonanal) and n-alkylketones (16.0% - 53.7% for hexan-2-one to nonan-2-one) with retention of excellent (S)- enantioselectivity (>99% ee). Complementary to the reported (R)- selective AmDHs, the promising mutant CfusAmDH-W145A was further characterized for its synthetic potential. Crystal structure resolution and molecular dynamics gave insights into the cofactor and substrate specificity and the whole structural dynamics, thus providing keys for mutagenesis work on this enzyme family

Published
2022
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8. Detection and Characterization of VIM-52, a New Variant of VIM-1 from a Klebsiella pneumoniae Clinical Isolate

Author

Te-Din Huang, Eddy Elisée, Pierre Sacré, Pierre Bogaerts, Paola Sandra Mercuri, Bogdan I. Iorga, Marie de Barsy, Moreno Galleni, Saoussen Oueslati, Thierry Naas, Université Catholique de Louvain = Catholic University of Louvain (UCL), Integrative Biological Sciences (InBioS), Université de Liège, Structure, Dynamique, Fonction Et Expression Des Beta-Lactamases À Large Spectre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Centre National de Référence de la Résistance aux Antibiotiques (CNR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), PSM and MG were supported by financial support from the University of Liege, from the Belgian Federal Public Service Health, Food Chain Safety and Environment [grant number RF 17/6317 RU-BLA-ESBL-CPE] and from the Belgian Fund for Scientific Research (F.R.S.-FNRS) (Grant 35328039).MdB, T-DH, PB, PS were supported by JPIAMR transnational project DesInMBL Structure-guided design of pan inhibitors of metallo-beta-lactamases Fonds de la recherche scientifique FNRS N° R.50.01.15.FBII, and EE were supported by the CNRS, Université Paris-Saclay, the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) through grants from the French National Research Agency (ANR-10-LABX-33), and by the JPIAMR transnational project DesInMBL (ANR-14-JAMR-0002).TN, SO were supported by the Assistance Publique-Hôpitaux de Paris, the Université Paris-Saclay, the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) through grants from the French National Research Agency (ANR- 10-LABX-33, ANR-17-ASTR-0018), and by the JPIAMR transnational project DesInMBL (ANR-14-JAMR-0002)., IORGA, Bogdan, and Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
Klebsiella pneumoniae, Cefepime, Ceftazidime, Microbial Sensitivity Tests, beta-Lactamases, Microbiology, 03 medical and health sciences, Antibiotic resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Mechanisms of Resistance, medicine, polycyclic compounds, Pharmacology (medical), 030304 developmental biology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, biology, 030306 microbiology, Mutagenesis, Active site, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Anti-Bacterial Agents, Infectious Diseases, Enzyme, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacteria, medicine.drug
Abstract

International audience; Over the last two decades, antimicrobial resistance has become a global health problem. In Gram-negative bacteria, metallo-β-lactamases (MBLs), which inactivate virtually all β-lactams, increasingly contribute to this phenomenon. The aim of this study is to characterize VIM-52, a His224Arg variant of VIM-1, identified in a Klebsiella pneumoniae clinical isolate. VIM-52 conferred lower MICs to cefepime and ceftazidime as compared to VIM-1. These results were confirmed by steady state kinetic measurements, where VIM-52 yielded a lower activity towards ceftazidime and cefepime but not against carbapenems. Residue 224 is part of the L10 loop (residues 221-241), which borders the active site. As Arg 224 and Ser 228 are both playing an important and interrelated role in enzymatic activity, stability and substrate specificity for the MBLs, targeted mutagenesis at both positions were performed and further confirmed their crucial role for substrate specificity.

Published
2021
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9. Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D)

Author

Mohamed Benchekroun, Saoussen Oueslati, Sandrine Ventre, Kamsana Vijayakumar, Eddy Elisée, Laetitia A. Nguyen, Edithe Selwa, Robert H. Dodd, Linda Tlili, Alain Pruvost, Pascal Retailleau, Thierry Naas, Agustin Zavala, Bogdan I. Iorga, Agathe C. A. D'Hollander, Eugénie Romero, Cynthia Exilie, Kevin Cariou, Corinne Minard, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT, grant ANR-10-LABX-33 under the program Investissements d’Avenir ANR-11-IDEX-0003-01), the FCS Campus Paris-Saclay pre-maturation program (project Inhibase), the SATT Paris-Saclay (project CARBAMAT), the JPIAMR transnational project DesInMBL (grant ANR-14-JAMR-0002) and the Région Ile-de-France (DIM Malinf). The authors also thank CNRS, AP-HP, Université Paris-Saclay, and ICSN, for financial support., ANR-10-LABX-0033,LERMIT,Research Laboratory on Drugs and Therapeutic Innovation(2010), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014), Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Cariou, Kevin, Research Laboratory on Drugs and Therapeutic Innovation - - LERMIT2010 - ANR-10-LABX-0033 - LABX - VALID, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, and programmation conjointe européenne sur la résistance antimicrobienne - Structure-guided design of pan inhibitors of metallo-ß-lactamases - - DesInMBL2014 - ANR-14-JAMR-0002 - JPI AMR - VALID

Subjects
Imipenem, Non covalent, Antibiotics, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, 01 natural sciences, Broad spectrum, Catalytic Domain, Drug Discovery, polycyclic compounds, OXA-48, chemistry.chemical_classification, 0303 health sciences, biology, Escherichia coli Proteins, General Medicine, Ynamides, Anti-Bacterial Agents, Molecular Docking Simulation, Microsomes, Liver, beta-Lactamase Inhibitors, medicine.drug, Gram-negative bacteria, Carbapenemase inhibitors, medicine.drug_class, Stereochemistry, Azetidinimines, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Microbial Sensitivity Tests, NDM-1, beta-Lactamases, Bacterial resistance, KPC-2, Cell Line, Inhibitory Concentration 50, Structure-Activity Relationship, 03 medical and health sciences, Antibiotic resistance, Gram-Negative Bacteria, medicine, Humans, Escherichia coli, Cell Proliferation, 030304 developmental biology, Pharmacology, Binding Sites, 010405 organic chemistry, Organic Chemistry, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, 0104 chemical sciences, Enzyme, chemistry, Azetidines
Abstract

International audience; The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient β-lactamases which render most β-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of β-lactams (namely azetidinimines) as efficient non-covalent inhibitors of β-lactamases. Despite the structural and mechanistic differences between serine-β-lactamases KPC-2 and OXA-48 and metallo-β-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki’s below 0.3 μM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 μM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of β-lactamases.

Published
2021
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10. Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases of classes A, B and D

Author

Linda Tlili, Thierry Naas, Eddy Elisée, Robert H. Dodd, Mohamed Benchekroun, Agustin Zavala, Eugénie Romero, Alain Pruvost, Corinne Minard, Agathe C.A. D'Hollander, Kevin Cariou, Saoussen Oueslati, Bogdan I. Iorga, Cynthia Exilie, Sandrine Ventre, Kamsana Vijayakumar, Edithe Selwa, Pascal Retailleau, Laetitia Nguyen, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Structure, Dynamique, Fonction Et Expression Des Beta-Lactamases À Large Spectre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Centre National de Référence de la Résistance aux Antibiotiques (CNR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CEA- Saclay (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Imipenem, Gram-negative bacteria, medicine.drug_class, Stereochemistry, Non covalent, Antibiotics, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, Broad spectrum, Antibiotic resistance, polycyclic compounds, medicine, Escherichia coli, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, 010405 organic chemistry, biology.organism_classification, 0104 chemical sciences, 3. Good health, Enzyme, chemistry, medicine.drug
Abstract

The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are indeed excellent β-lactamase inhibitors and that our lead compound can inhibit NDM-1 (0.1 µM), KPC-2 (0.4 µM), and OXA-48 (0.6 µM) even though these three enzymes belong to three different molecular classes of carbapenemases. This lead compound also inhibits the ESBL CTX-M-15 and the cephalosporinase CMY-2, it is metabolically stable, and can repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1.

Published
2020

11. Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Author

Bogdan I. Iorga, Ludovic Chaput, Bert L. de Groot, Nawel Mele, Eddy Elisée, Vytautas Gapsys, Edithe Selwa, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée (CoRaKID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Research reported in this publication was supported by grants ANR-10-LABX-33 (LabEx LERMIT) and ANR-14-JAMR-0002 (JPIAMR) from the French National Research Agency (ANR), by the Région Ile-de-France (DIM Malinf), by the Université Paris- Saclay (Globetalkers 2019) and by European Research Council grant ERC-2012-ADG_20120314 (Grant Agreement 322947)., ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014), European Project: 322947,EC:FP7:ERC,ERC-2012-ADG_20120314,OSAI(2013), IORGA, Bogdan, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, programmation conjointe européenne sur la résistance antimicrobienne - Structure-guided design of pan inhibitors of metallo-ß-lactamases - - DesInMBL2014 - ANR-14-JAMR-0002 - JPI AMR - VALID, Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI) - OSAI - - EC:FP7:ERC2013-05-01 - 2018-04-30 - 322947 - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Common and Rare Kidney Diseases = Maladies Rénales Fréquentes et Rares: des Mécanismes Moléculaires à la Médecine Personnalisée (CORAKID)

Subjects
Protein Conformation, Computer science, Entropy, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Crystallography, X-Ray, Ligands, computer.software_genre, 01 natural sciences, Molecular dynamics, Software, 0103 physical sciences, Drug Discovery, Humans, Physical and Theoretical Chemistry, Binding Sites, 010304 chemical physics, business.industry, 0104 chemical sciences, Computer Science Applications, Molecular Docking Simulation, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, 010404 medicinal & biomolecular chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, Workflow, Docking (molecular), Drug Design, Computer-Aided Design, Thermodynamics, Data mining, business, computer, Protein Binding
Abstract

International audience; Using the D3R Grand Challenge 4 dataset containing Beta-secretase 1 (BACE) and Cathepsin S (CatS) inhibitors, we have evaluated the performance of our in-house docking workflow that involves in the first step the selection of the most suitable docking software for the system of interest based on structural and functional information available in public databases, followed by the docking of the dataset to predict the binding modes and ranking of ligands. The macrocyclic nature of the BACE ligands brought additional challenges, which were dealt with by a careful preparation of the three-dimensional input structures for ligands. This provided top-performing predictions for BACE, in contrast with CatS, where the predictions in the absence of guiding constraints provided poor results. These results highlight the importance of previous structural knowledge that is needed for correct predictions on some challenging targets. After the end of the challenge, we also carried out free energy calculations (i.e. in a non-blinded manner) for CatS using the pmx software and several force fields (AMBER, Charmm). Using knowledge-based starting pose construction allowed reaching remarkable accuracy for the CatS free energy estimates. Interestingly, we show that the use of a consensus result, by averaging the results from different force fields, increases the prediction accuracy.

Published
2019
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12. Blinded evaluation of cathepsin S inhibitors from the D3RGC3 dataset using molecular docking and free energy calculations

Author

Eddy Elisée, Ludovic Chaput, Bogdan I. Iorga, Edithe Selwa, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Région Ile-de-France (Conseil Régional, Île-de-France, DIM Malinf), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014), IORGA, Bogdan, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, programmation conjointe européenne sur la résistance antimicrobienne - Structure-guided design of pan inhibitors of metallo-ß-lactamases - - DesInMBL2014 - ANR-14-JAMR-0002 - JPI AMR - VALID, and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Computer science, Protein Data Bank (RCSB PDB), Computational biology, Molecular Dynamics Simulation, Crystallography, X-Ray, Ligands, 01 natural sciences, 03 medical and health sciences, Molecular dynamics, Structure-Activity Relationship, 0103 physical sciences, Drug Discovery, Physical and Theoretical Chemistry, Enzyme Inhibitors, Databases, Protein, ComputingMilieux_MISCELLANEOUS, Binding Sites, 010304 chemical physics, Molecular Structure, chEMBL, Cathepsins, Computer Science Applications, Molecular Docking Simulation, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, 030104 developmental biology, Docking (molecular), Drug Design, Solvents, Computer-Aided Design, Thermodynamics, BindingDB, PubChem, Protein Binding
Abstract

During the last few years, we have developed a docking protocol involving two steps: (i) the choice of the most appropriate docking software and parameters for the system of interest using structural and functional information available in public databases (PDB, ChEMBL, PubChem Assay, BindingDB, etc.); (ii) the docking of ligand dataset to provide a prediction for the binding modes and ranking of ligands. We applied this protocol to the D3R Grand Challenge 3 dataset containing cathepsin S (CatS) inhibitors. Considering the size and conformational flexibility of ligands, the docking calculations afforded reasonable overall pose predictions, which are however dependent on the specific nature of each ligand. As expected, the correct ranking of docking poses is still challenging. Post-processing of docking poses with molecular dynamics simulations in explicit solvent provided a significantly better prediction, whereas free energy calculations on a subset of compounds brought no significant improvement in the ranking prediction compared with the direct ranking obtained from the scoring function.

Published
2019
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13. Blinded evaluation of farnesoid X receptor (FXR) ligands binding using molecular docking and free energy calculations

Author

Eddy Elisée, Edithe Selwa, Agustin Zavala, Bogdan I. Iorga, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), and ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014)

Subjects
0301 basic medicine, Protein Conformation, Protein Data Bank (RCSB PDB), Receptors, Cytoplasmic and Nuclear, Computational biology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Ligands, 01 natural sciences, Molecular Docking Simulation, Force field (chemistry), Small Molecule Libraries, 03 medical and health sciences, Chemical Moiety, Farnesoid X receptor, Drug Discovery, scoring function, Humans, Drug Design Data Resource, Spiro Compounds, Physical and Theoretical Chemistry, Databases, Protein, Simulation, Autodock, Sulfonamides, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Grand Challenge 2 2, Isoxazoles, AutoDock, 0104 chemical sciences, Computer Science Applications, 010404 medicinal & biomolecular chemistry, 030104 developmental biology, Protein–ligand docking, FXR, Docking (molecular), Drug Design, Vina, docking, Thermodynamics, Benzimidazoles, Gold, Software, D3R, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Protein Binding
Abstract

This work was supported by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) [grant number ANR-10-LABX-33], by the JPIAMR transnational project DesInMBL [grant number ANR-14-JAMR-0002] and by the Région Ile-de-France (DIM Malinf).; International audience; Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions. Our free energy calculations on two different subsets provided contrasted results, which might have the origin in non-optimal force field parameters associated with the sulfonamide chemical moiety.

Published
2018
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