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An information gain-based approach for evaluating protein structure models

Guillaume Postic, Nathalie Janel, Pierre Tufféry, Gautier Moroy
2020 Computational and Structural Biotechnology Journal  
Gautier Moroy: Formal analysis, Validation, Writing -original draft, Writing -review & editing.  ... 
doi:10.1016/j.csbj.2020.08.013 pmid:32837711 pmcid:PMC7431362 fatcat:lrx7pcewmra63mzn3aq3uxhcee

JNK Contributes to Hif-1α Regulation in Hypoxic Neurons

Xanthi Antoniou, Alessandra Sclip, Cristina Ploia, Alessio Colombo, Gautier Moroy, Tiziana Borsello
2009 Molecules  
Hypoxia is an established factor of neurodegeneration. Nowadays, attention is directed at understanding how alterations in the expression of stress-related signaling proteins contribute to age dependent neuronal vulnerability to injury. The purpose of this study was to investigate how Hif-1α, a major neuroprotective factor, and JNK signaling, a key pathway in neurodegeneration, relate to hypoxic injury in young (6DIV) and adult (12DIV) neurons. We could show that in young neurons as compared to
more » ... mature ones, the protective factor Hif-1α is more induced while the stress protein phospho-JNK displays lower basal levels. Indeed, changes in the expression levels of these proteins correlated with increased vulnerability of adult neurons to hypoxic injury. Furthermore, we describe for the first time that treatment with the D-JNKI1, a JNK-inhibiting peptide, rescues adult hypoxic neurons from death and contributes to Hif-1α upregulation, probably via a direct interaction with the Hif-1α protein.
doi:10.3390/molecules15010114 pmid:20110876 pmcid:PMC6256924 fatcat:4gq4m434yret5et53ldfriukcm

Pharmacomodulation of Broad Spectrum Matrix Metalloproteinase Inhibitors Towards Regulation of Gelatinases [chapter]

Erika Bourguet, William Hornebeck, Janos Sapi, Alain Jean-Paul, Gautier Moroy
2012 Enzyme Inhibition and Bioapplications  
To that end, an oleoyl group was incorporated to galardin ® at the P'3 position ( Figure 9 ) (Moroy et al., 2011) .  ...  Advantageously, as we recently documented, oleoyl moiety might be replaced by -lactam (Moroy et al., 2012) , a more potent and selective HLE inhibitor.  ... 
doi:10.5772/35412 fatcat:mx7t4i4hrzf2pm2hbza5pgh7y4

Toward in silico structure-based ADMET prediction in drug discovery

Gautier Moroy, Virginie Y. Martiny, Philippe Vayer, Bruno O. Villoutreix, Maria A. Miteva
2012 Drug Discovery Today  
Quantitative structure-activity relationship (QSAR) methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. As the three-dimensional structures of several major ADMET proteins become available, structure-based (docking-scoring) computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging
more » ... ocess because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported. After reviewing current trends in the field we applied structure-based methods in the context of receptor flexibility in a case study involving the phase II metabolizing sulfotransferases. Overall, the explored concepts and results suggested that structure-based ADMET profiling will probably join the mainstream during the coming years. Reviews INFORMATICS Corresponding author:. Miteva, M.A. (maria.miteva@univ-paris-diderot.fr) 44 www.drugdiscoverytoday.com
doi:10.1016/j.drudis.2011.10.023 pmid:22056716 fatcat:jiela55gcra6zpwhsbttc7d64i

Catechins as a Potential Dietary Supplementation in Prevention of Comorbidities Linked with Down Syndrome

Christophe Noll, Janany Kandiah, Gautier Moroy, Yuchen Gu, Julien Dairou, Nathalie Janel
2022 Nutrients  
Plant-derived polyphenols flavonoids are increasingly being recognized for their medicinal potential. These bioactive compounds derived from plants are gaining more interest in ameliorating adverse health risks because of their low toxicity and few side effects. Among them, therapeutic approaches demonstrated the efficacy of catechins, a major group of flavonoids, in reverting several aspects of Down syndrome, the most common genomic disorder that causes intellectual disability. Down syndrome
more » ... characterized by increased incidence of developing Alzheimer's disease, obesity, and subsequent metabolic disorders. In this focused review, we examine the main effects of catechins on comorbidities linked with Down syndrome. We also provide evidence of catechin effects on DYRK1A, a dosage-sensitive gene encoding a protein kinase involved in brain defects and metabolic disease associated with Down syndrome.
doi:10.3390/nu14102039 fatcat:fayizoht7rhqtlxiapioyrioje

In Silico Mechanistic Profiling to Probe Small Molecule Binding to Sulfotransferases

Virginie Y. Martiny, Pablo Carbonell, David Lagorce, Bruno O. Villoutreix, Gautier Moroy, Maria A. Miteva, Daniel S. Sem
2013 PLoS ONE  
Drug metabolizing enzymes play a key role in the metabolism, elimination and detoxification of xenobiotics, drugs and endogenous molecules. While their principal role is to detoxify organisms by modifying compounds, such as pollutants or drugs, for a rapid excretion, in some cases they render their substrates more toxic thereby inducing severe side effects and adverse drug reactions, or their inhibition can lead to drug-drug interactions. We focus on sulfotransferases (SULTs), a family of phase
more » ... II metabolizing enzymes, acting on a large number of drugs and hormones and showing important structural flexibility. Here we report a novel in silico structure-based approach to probe ligand binding to SULTs. We explored the flexibility of SULTs by molecular dynamics (MD) simulations in order to identify the most suitable multiple receptor conformations for ligand binding prediction. Then, we employed structure-based docking-scoring approach to predict ligand binding and finally we combined the predicted interaction energies by using a QSAR methodology. The results showed that our protocol successfully prioritizes potent binders for the studied here SULT1 isoforms, and give new insights on specific molecular mechanisms for diverse ligands' binding related to their binding sites plasticity. Our best QSAR models, introducing predicted protein-ligand interaction energy by using docking, showed accuracy of 67.28%, 78.00% and 75.46%, for the isoforms SULT1A1, SULT1A3 and SULT1E1, respectively. To the best of our knowledge our protocol is the first in silico structure-based approach consisting of a protein-ligand interaction analysis at atomic level that considers both ligand and enzyme flexibility, along with a QSAR approach, to identify small molecules that can interact with II phase dug metabolizing enzymes.
doi:10.1371/journal.pone.0073587 pmid:24039991 pmcid:PMC3765257 fatcat:nuh4s5jcnncyrk3vwglvkfwqla

Integrated structure- and ligand-basedin silicoapproach to predict inhibition of cytochrome P450 2D6

Virginie Y. Martiny, Pablo Carbonell, Florent Chevillard, Gautier Moroy, Arnaud B. Nicot, Philippe Vayer, Bruno O. Villoutreix, Maria A. Miteva
2015 Bioinformatics  
., 2013; Moroy et al., 2012; Stoll et al., 2011; Tyzack et al., 2013) .  ...  However, the extensive flexibility of the CYP2D6 structure, which represents its natural mechanism to accommodate diverse ligands into the active site (Moroy et al., 2012; Wang et al., 2015) , can strongly  ... 
doi:10.1093/bioinformatics/btv486 pmid:26315915 fatcat:wtbuobphbfdhjgrypmc5caibdq

SeamDock: An Interactive and Collaborative Online Docking Resource to Assist Small Compound Molecular Docking

Samuel Murail, Sjoerd J. de Vries, Julien Rey, Gautier Moroy, Pierre Tufféry
2021 Frontiers in Molecular Biosciences  
Copyright © 2021 Murail, de Vries, Rey, Moroy and Tufféry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
doi:10.3389/fmolb.2021.716466 pmid:34604303 pmcid:PMC8484321 fatcat:ahts2gv6n5durc7mdxxv6vldxe

Molecular Basis for Bcl-2 Homology 3 Domain Recognition in the Bcl-2 Protein Family

Gautier Moroy, Elyette Martin, Annick Dejaegere, Roland H. Stote
2009 Journal of Biological Chemistry  
The proteins of the Bcl-2 family are important regulators of apoptosis, or programmed cell death. These proteins regulate this fundamental biological process via the formation of heterodimers involving both pro-and anti-apoptotic family members. Disruption of the balance between anti-and pro-apoptotic Bcl-2 proteins is the cause of numerous pathologies. Bcl-xl, an anti-apoptotic protein of this family, is known to form heterodimers with multiple pro-apoptotic proteins, such as Bad, Bim, Bak,
more » ... Bid. To elucidate the molecular basis of this recognition process, we used molecular dynamics simulations coupled with the Molecular Mechanics/Poisson-Boltzmann Surface Area approach to identify the amino acids that make significant energetic contributions to the binding free energy of four complexes formed between Bcl-xl and pro-apoptotic Bcl-2 homology 3 peptides. A fifth protein-peptide complex composed of another anti-apoptotic protein, Bcl-w, in complex with the peptide from Bim was also studied. The results identified amino acids of both the anti-apoptotic proteins as well as the Bcl-2 homology 3 (BH3) domains of the pro-apoptotic proteins that make strong, recurrent interactions in the protein complexes. The calculations show that the two anti-apoptotic proteins, Bcl-xl and Bcl-w, share a similar recognition mechanism. Our results provide insight into the molecular basis for the promiscuous nature of this molecular recognition process by members of the Bcl-2 protein family. These amino acids could be targeted in the design of new mimetics that serve as scaffolds for new antitumoral molecules. Downloaded from a BH3 peptide and its amino acid length are shown. b AA means amino acid. c This is the absolute value of the amino acid efficiency.
doi:10.1074/jbc.m805542200 pmid:19293158 pmcid:PMC2788401 fatcat:iwq5kz3lcbfp7d3gprpu2nioeq

PEP-SiteFinder: a tool for the blind identification of peptide binding sites on protein surfaces

Adrien Saladin, Julien Rey, Pierre Thévenet, Martin Zacharias, Gautier Moroy, Pierre Tufféry
2014 Nucleic Acids Research  
Peptide-protein interactions are important to many processes of life, particularly for signal transmission or regulatory mechanisms. When no information is known about the interaction between a protein and a peptide, it is of interest to propose candidate sites of interaction at the protein surface, to assist the design of biological experiments to probe the interaction, or to serve as a starting point for more focused in silico approaches. PEP-SiteFinder is a tool that will, given the
more » ... of a protein and the sequence of a peptide, identify protein residues predicted to be at peptide-protein interface. PEP-SiteFinder relies on the 3D de novo generation of peptide conformations given its sequence. These conformations then undergo a fast blind rigid docking on the complete protein surface, and we have found, as the result of a benchmark over 41 complexes, that the best poses overlap to some extent the experimental patch of interaction for close to 90% complexes. In addition, PEP-SiteFinder also returns a propensity index we have found informative about the confidence of the prediction. The PEP-SiteFinder web server is available at http://bioserv.rpbs.univ-paris-diderot.fr/PEP-SiteFinder.
doi:10.1093/nar/gku404 pmid:24803671 pmcid:PMC4086095 fatcat:g3s25e5s3rcd3aaxelstwzktcu

Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations

Mariem Ghoula, Nathalie Janel, Anne-Claude Camproux, Gautier Moroy
2022 International Journal of Molecular Sciences  
Insulin-degrading enzyme (IDE) is a ubiquitously expressed metallopeptidase that degrades insulin and a large panel of amyloidogenic peptides. IDE is thought to be a potential therapeutic target for type-2 diabetes and neurodegenerative diseases, such as Alzheimer's disease. IDE catalytic chamber, known as a crypt, is formed, so that peptides can be enclosed and degraded. However, the molecular mechanism of the IDE function and peptide recognition, as well as its conformation changes, remains
more » ... usive. Our study elucidates IDE structural changes and explains how IDE conformational dynamics is important to modulate the catalytic cycle of IDE. In this aim, a free-substrate IDE crystallographic structure (PDB ID: 2JG4) was used to model a complete structure of IDE. IDE stability and flexibility were studied through molecular dynamics (MD) simulations to witness IDE conformational dynamics switching from a closed to an open state. The description of IDE structural changes was achieved by analysis of the cavity and its expansion over time. Moreover, the quasi-harmonic analysis of the hinge connecting IDE domains and the angles formed over the simulations gave more insights into IDE shifts. Overall, our results could guide toward the use of different approaches to study IDE with different substrates and inhibitors, while taking into account the conformational states resolved in our study.
doi:10.3390/ijms23031746 pmid:35163673 pmcid:PMC8836115 fatcat:c3u24oqvhncbzndnw4qdvlzxry

Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity

Lydia Benkaidali, François André, Gautier Moroy, Bahoueddine Tangour, François Maurel, Michel Petitjean
2019 International Journal of Molecular Sciences  
We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of
more » ... tion of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data.
doi:10.3390/ijms20040987 fatcat:2nzspzxdefcgvhfhdrmm2o44qq

A rational free energy-based approach to understanding and targeting disease-causing missense mutations

Zhe Zhang, Shawn Witham, Marharita Petukh, Gautier Moroy, Maria Miteva, Yoshihiko Ikeguchi, Emil Alexov
2013 JAMIA Journal of the American Medical Informatics Association  
and significance Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and
more » ... D is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society. Objective To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects. Methods Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy. Results It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site. Conclusions This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.
doi:10.1136/amiajnl-2012-001505 pmid:23408511 pmcid:PMC3721167 fatcat:5mih3em4pvbtnjfash6wyugdzy

Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins

Yuchen Gu, Gautier Moroy, Jean-Louis Paul, Anne-Sophie Rebillat, Mara Dierssen, Rafael de la Torre, Cécile Cieuta-Walti, Julien Dairou, Nathalie Janel
2020 International Journal of Molecular Sciences  
Epigallocatechin gallate (EGCG) is an inhibitor of DYRK1A, a serine/threonine kinase considered to be a major contributor of cognitive dysfunctions in Down syndrome (DS). Two clinical trials in adult patients with DS have shown the safety and efficacy to improve cognitive phenotypes using commercial green tea extract containing EGCG (45% content). In the present study, we performed a preclinical study using FontUp®, a new nutritional supplement with a chocolate taste specifically formulated for
more » ... the nutritional needs of patients with DS and enriched with a standardized amount of EGCG in young mice overexpressing Dyrk1A (TgBACDyrk1A). This preparation is differential with previous one used, because its green tea extract has been purified to up 94% EGCG of total catechins. We analyzed the in vitro effect of green tea catechins not only for EGCG, but for others residually contained in FontUp®, on DYRK1A kinase activity. Like EGCG, epicatechin gallate was a noncompetitive inhibitor against ATP, molecular docking computations confirming these results. Oral FontUp® normalized brain and plasma biomarkers deregulated in TgBACDyrk1A, without negative effect on liver and cardiac functions. We compared the bioavailability of EGCG in plasma and brain of mice and have demonstrated that EGCG had well crossed the blood-brain barrier.
doi:10.3390/ijms21041404 pmid:32092951 pmcid:PMC7073110 fatcat:urcuvik7bnh7ncjgvkvxyslbd4

Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis

Gautier Moroy, Olivier Sperandio, Shakti Rielland, Saurabh Khemka, Karen Druart, Divij Goyal, David Perahia, Maria A Miteva
2015 Future Medicinal Chemistry  
Aim: Molecular dynamics simulations and normal mode analysis are well-established approaches to generate receptor conformational ensembles (RCEs) for ligand docking and virtual screening. Here, we report new fast molecular dynamics-based and normal mode analysis-based protocols combined with conformational pocket classifications to efficiently generate RCEs. Materials \& methods: We assessed our protocols on two well-characterized protein targets showing local active site flexibility,
more » ... ate reductase and large collective movements, CDK2. The performance of the RCEs was validated by distinguishing known ligands of dihydrofolate reductase and CDK2 among a dataset of diverse chemical decoys. Results \& discussion: Our results show that different simulation protocols can be efficient for generation of RCEs depending on different kind of protein flexibility.
doi:10.4155/fmc.15.150 pmid:26599419 fatcat:f23jonpdnrbzfknpz4djvbytvi
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