Three-dimensional structural model of epoxide hydrolase (PchEHA) from Phanerochaete chrysosporium was constructed based on X-ray structure of Agrobacterium radiobacter AD1 sEH using SWISS-MODEL server. Conserved residues constituting the... more
Three-dimensional structural model of epoxide hydrolase (PchEHA) from Phanerochaete chrysosporium was constructed based on X-ray structure of Agrobacterium radiobacter AD1 sEH using SWISS-MODEL server. Conserved residues constituting the active site cavity were identified, of which the functional roles of 14 residues were determined by site-directed mutagenesis. In catalytic triad, Asp105 and His308 play a leading role in alkylation and hydrolysis steps, respectively. Distance between Asp105 and epoxide ring of substrate may determine the regiospecificity in the substrate docking model. Asp277 located at the entrance of substrate tunnel is concerned with catalysis but not essential. D307E had the highest activity and lower enantioselectivity among 14 mutants, suggesting Asp307 may be involved in choice of substrate configuration. Y159F and Y241F almost exhibited no activity, indicating that they are essential to bind substrate and facilitate opening of epoxide ring. Besides, His35-Gly36-Asn37-Pro38, Trp106 and Trp309 surrounding Asp105, may coordinate the integration of active site cavity and influence substrate binding. Especially, W106I reversed the enantioselectivity, perhaps due to more deteriorative impact on the preferred (R)-styrene oxide. Gly65 and Gly67 occurring at β-turns and Gly36 are vital in holding protein conformation. Conclusively, single conserved residue around the active sites has an important impact on catalytic properties.
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We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural... more
We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a "jaw opening" gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest K i at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.
Research Interests: Microbiology, Computer Science, Molecular Dynamics Simulation, Computational Biology, Medical Microbiology, and 15 moreBiology, Medicine, Humans, Animals, Chagas disease, Swine, THEORETICAL AND COMPUTATIONAL CHEMISTRY, Triazoles, In Silico, Structure activity Relationship, Protein Binding, Molecular Structure, binding sites, Sulfonamides, and Pharmacology and pharmaceutical sciences
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Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Magnetic Resonance Spectroscopy, Medicine, and 14 moreFluorescence Resonance Energy Transfer, Cell line, Humans, Mice, Animals, Stereochemistry, Drug Design, Enzyme, Coumarins, Protease Inhibitors, Medicinal, Structure activity Relationship, Piperazine, and Pharmacology and pharmaceutical sciences
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The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted... more
The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin rec...
Research Interests: Kinetics, Biology, Biological Chemistry, Medicine, Biological Sciences, and 15 moreHumans, Mutation, Animals, Biological, Neurons, CHEMICAL SCIENCES, Amino Acid Sequence, Cholecystokinin, Ligands, Binding Site, Agonist, Molecular Sequence Data, Inositol Phosphates, binding sites, and Medical and Health Sciences
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ABSTRACT
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We describe selective CCKA receptor antagonists, based on the 1-oxo-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid core. Selectivity A vs B is discussed on the basis of molecular modelling. Chemical preparation uses electrophilic... more
We describe selective CCKA receptor antagonists, based on the 1-oxo-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid core. Selectivity A vs B is discussed on the basis of molecular modelling. Chemical preparation uses electrophilic cyclization of isocyanates derivating from unnatural tryptophan esters. A stereoselective version of the reaction is given. A few peptides incorporating unnatural tryptophans are prepared, with a view of SAR.
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HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come from teaching and research institutions in France or abroad,... more
HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et a ̀ la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Dynamic interface between proteins?
Growth of the lactic acid bacterium Streptococcus thermophilus in milk depends on its capacity to hydrolyze proteins of this medium through its surface proteolytic activity. Thus, strains exhibiting the cell envelope proteinase (CEP) PrtS... more
Growth of the lactic acid bacterium Streptococcus thermophilus in milk depends on its capacity to hydrolyze proteins of this medium through its surface proteolytic activity. Thus, strains exhibiting the cell envelope proteinase (CEP) PrtS are able to grow in milk at high cellular density. Due to its LPNTG motif, which is possibly the substrate of the sortase A (SrtA), PrtS is anchored to the cell wall in most S. thermophilus strains. Conversely, a soluble extracellular PrtS activity has been reported in the strain 4F44. It corresponds, in fact, to a certain proportion of PrtS that is not anchored to the cell wall but rather is released in the growth medium. The main difference between PrtS of strain 4F44 (PrtS4F44) and other PrtS concerns the absence of a 32-residue imperfect duplication in the prodomain of the CEP, postulated as being required for the maturation and correct subsequent anchoring of PrtS. In fact, both mature (without the prodomain at the N-terminal extremity) and im...
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By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space,... more
By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC 50 of 7.2 μ M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway betw...
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Root-knot nematodes (RKN), from the Meloidogyne genus, have a worldwide distribution and cause severe economic damage to many life-sustaining crops. Because of their lack of specificity and danger to the environment, most chemical... more
Root-knot nematodes (RKN), from the Meloidogyne genus, have a worldwide distribution and cause severe economic damage to many life-sustaining crops. Because of their lack of specificity and danger to the environment, most chemical nematicides have been banned from use. Thus, there is a great need for new and safe compounds to control RKN. Such research involves identifying beforehand the nematode proteins essential to the invasion. Since G protein-coupled receptors GPCRs are the target of a large number of drugs, we have focused our research on the identification of putative nematode GPCRs such as those capable of controlling the movement of the parasite towards (or within) its host. A datamining procedure applied to the genome of Meloidogyne incognita allowed us to identify a GPCR, belonging to the neuropeptide GPCR family that can serve as a target to carry out a virtual screening campaign. We reconstructed a 3D model of this receptor by homology modeling and validated it through ...
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Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an... more
Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds b...
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Many of the modeling targets in the blind CASP-11/CAPRI-30 experiment were protein homo-dimers and homo-tetramers. Here, we perform a retrospective docking-based analysis of the perfectly symmetrical CAPRI Round 30 targets whose crystal... more
Many of the modeling targets in the blind CASP-11/CAPRI-30 experiment were protein homo-dimers and homo-tetramers. Here, we perform a retrospective docking-based analysis of the perfectly symmetrical CAPRI Round 30 targets whose crystal structures have been published. Starting from the CASP "stage-2" fold prediction models, we show that using our recently developed "SAM" polar Fourier symmetry docking algorithm combined with NAMD energy minimisation often gives acceptable or better 3D models of the target complexes. We also use SAM to analyse the overall quality of all CASP structural models for the selected targets from a docking-based perspective. We demonstrate that docking only CASP "centre" structures for the selected targets provides a fruitful and economical docking strategy. Furthermore, our results show that many of the CASP models are dockable in the sense that they can lead to acceptable or better models of symmetrical complexes.Even though S...
Research Interests: Computer Science, Algorithms, Thermodynamics, Research Design, Computational Biology, and 14 moreBenchmarking, Medicine, Macromolecular X-Ray Crystallography, Biological Sciences, Software, Protein Docking, Mathematical Sciences, Proteins, CAPRI, Protein Conformation, Protein Modeling, Protein Binding, CASP, and binding sites
Research Interests: Chemistry, Organic Chemistry, Molecular modeling, Humans, Peptidomimetics, and 10 moreVEGF, CARBOHYDRATES, Bioorganic and medicinal Chemistry, Cell Proliferation, Structure activity Relationship, Cell Survival, Neuropilin, Molecular Structure, Pharmacology and pharmaceutical sciences, and Human Umbilical Vein Endothelial Cells
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We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst... more
We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein-protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with...
Research Interests: Computer Science, Algorithms, Thermodynamics, Molecular Dynamics Simulation, Protein Folding, and 14 moreComputational Biology, International Cooperation, Medicine, Biological Sciences, Software, Humans, Protein Docking, Mathematical Sciences, Bacteria, Proteins, Protein Binding, Internet, CASP, and binding sites
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The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological... more
The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to "nonselective" interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lu...
Research Interests: Molecular Dynamics Simulation, Biology, Enzyme Inhibitors, Medicine, Multidisciplinary, and 13 moreCell line, Mice, Animals, Cell Death, PLoS one, Thioredoxin, Antifungal Agents, Microbial Sensitivity Tests, Recombinant Proteins, Biological Assay, Ligands, Paracoccidioides, and Thioredoxin reductase
Abstract Ab initio calculations are performed to evaluate molecular properties of 4- and 5-methylimidazole (MeIm) and the protonated form (MeImH + ) with extended basis sets ranging from 6-31G ∗ to 6-311 + +G ∗∗ at Hartree-Fock,... more
Abstract Ab initio calculations are performed to evaluate molecular properties of 4- and 5-methylimidazole (MeIm) and the protonated form (MeImH + ) with extended basis sets ranging from 6-31G ∗ to 6-311 + +G ∗∗ at Hartree-Fock, Moller-Plesset perturbation (MP2, MP3, MP4) and density functional (BLYP, B3LYP, B3PW91) levels. Optimized geometry structures, energies and thermochemical properties are carefully analysed. The geometries are not particularly sensitive to the basis set employed, but change appreciably when correlation effects are included. The tautomer equilibrium constant and the protonation energy are, in contrast, much more sensitive to both basis set and correlation effects, although good results are obtained at the simple MP2 level. The computationally less costly density functional (DF) method leads to results similar to those from MP2. The gas phase tautomer equilibrium constant and the protonation enthalpy of 4- and 5-MeIm are calculated at all levels. The results obtained with the 6-31+G ∗ , 6-311+G ∗ and 6-311++G ∗∗ basis sets at MP2 and DF levels are in excellent agreement with available experimental values.
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A comprehensive study of the naturally occurring amino acid side chains is presented. This includes a full ab initio SCF geometry optimization of each structure, using the 6-3 1G** split-valence basis set, and the derivation of net atomic... more
A comprehensive study of the naturally occurring amino acid side chains is presented. This includes a full ab initio SCF geometry optimization of each structure, using the 6-3 1G** split-valence basis set, and the derivation of net atomic charges from the molecular ...
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ABSTRACT The serotonin, h5-HT4 receptor is a G protein-coupled receptor (GPCR) known to be involved in a variety of pathological disorders such as irritable bowel syndrome, cardiac atrial arrhythmia and memory deficits. Recent studies... more
ABSTRACT The serotonin, h5-HT4 receptor is a G protein-coupled receptor (GPCR) known to be involved in a variety of pathological disorders such as irritable bowel syndrome, cardiac atrial arrhythmia and memory deficits. Recent studies have also underlined its potential role in Alzheimer’s disease. We present here the results of molecular dynamics simulations of h5-HT4 receptor binding a non-peptide antagonist ligand in a realistic membrane environment. The GPCR-bound ligand model built in vacuo using homology modelling of bovine rhodopsin and several experimental constraints [L. Rivail, et al., New insights into the human 5-HT4 receptor binding site: exploration of a hydrophobic pocket, Br. J. Pharmacol. 143(3) (2004) 361–370] was relaxed during 10 ns of constant pressure and constant temperature simulation. The results show that the receptor model is stable and that the key interactions formed with the ligand and identified experimentally are conserved. The simulations further reveal that several water molecules migrate from the extracellular milieu toward the putative hydrophobic pocket [L. Rivail, et al., New insights into the human 5-HT4 receptor binding site: exploration of a hydrophobic pocket, Br. J. Pharmacol. 143(3) (2004) 361–370; R. Bureau, et al., Molecular design based on 3D pharmacophore. Application to 5-HT4, J. Chem. Inform. Comput. Sci. (2001) A–F; M.L. Lopez-Rodriguez, et al., Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites. J. Comput. Aided Mol. Des. 11(6) (1997) 589–599] accommodating the ligand, and form a network of interactions with the receptor, hence underlining the limitations of the in vacuo construct. The refined three-dimensional model of the receptor can now be used for docking studies of other ligands, thereby helping the rational design of new drugs for h5-HT4.
Research Interests: Chemistry, Molecular modeling, Serotonin, GPCR, Irritable Bowel Syndrome, and 12 moreMolecular Model, Homology modelling, Three Dimensional, Receptor, Arrhythmia, Large Scale, Lipid Bilayer, Molecular Dynamic Simulation, Binding Site, Protein Ligand Interaction, Serotonin receptor, and Molecular dynamic
... MARIE-CLAUDE FOURNIE-ZALUSKI', GILLES GACEL', BERNARD MAIGRET2, SAMUEL PREMILAT,2 AND BERNARD P. RoQuEs' D#{233}partement de Chimie Organique ERA 613 du Centre National de la Recherche Scientifique et SCN 21 de... more
... MARIE-CLAUDE FOURNIE-ZALUSKI', GILLES GACEL', BERNARD MAIGRET2, SAMUEL PREMILAT,2 AND BERNARD P. RoQuEs' D#{233}partement de Chimie Organique ERA 613 du Centre National de la Recherche Scientifique et SCN 21 de l'Institut ...
Research Interests: Chemistry, Physical Chemistry, Magnetic Resonance Spectroscopy, Molecular Pharmacology, Medicine, and 10 moreMolecular, Animals, Central Nervous System, Rats, Receptor, Molecular Conformation, Structure activity Relationship, Neurosciences, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
The conformational behavior of the sterically restricted cyclic peptide Tyr-cyclo(-N gamma-D-A2-bu-Gly-Phe-Leu-), proposed recently as an enkephalin analog with high opiate activity, is examined by theoretical investigations. The method... more
The conformational behavior of the sterically restricted cyclic peptide Tyr-cyclo(-N gamma-D-A2-bu-Gly-Phe-Leu-), proposed recently as an enkephalin analog with high opiate activity, is examined by theoretical investigations. The method used allows the search of conformational energy minima associated with cyclic structures fitting a hypothetical opiate pharmacophore. The results obtained show that, despite the fact that many cyclic structures of low conformational energy can be found for this compound, only one of them can be retained as a conformer presenting the characteristic features of the imposed pharmacophore. This conformation is stabilized by an intramolecular H-bond between the D-A2bu-carbonyl and the Leu NH group so that a beta-turn is formed. This structure also presents a high mobility of the Tyr1 side-chain which can fit the tyramine moiety of rigid opiates with minor loss of conformational energy. A two-step binding mechanism is proposed for the interactions of this ...