Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors
| Autor: | Neha Tripathi, Mickael Jean, Patrick Legembre, Adèle D. Laurent, Iyanar Vetrivel, Stéphane Téletchéa |
|---|---|
| Přispěvatelé: | Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), PLBIO-2018, Institut National Contre le Cancer (INCa), Mim-Breg, Région Pays de la Loire, CE15-0027, Agence Nationale de la Recherche, 2017-2019 (PL), Fondation ARC pour la Recherche sur le Cancer, Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE15-0027,FASILE,Impact du CD95L, dans la dysfonction des lymphocytes T exprimant l'IL-17 au cours du lupus(2017), Jonchère, Laurent |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Molecular model
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] pharmacophore mapping Computational biology Phospholipase Phospholipase C gamma Article Catalysis SH3 domain lcsh:Chemistry Inorganic Chemistry phospholipase C gamma 1 03 medical and health sciences 0302 clinical medicine Protein Domains medicine Humans Enzyme Inhibitors Physical and Theoretical Chemistry lcsh:QH301-705.5 Molecular Biology Spectroscopy 030304 developmental biology 0303 health sciences Virtual screening [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Drug discovery Chemistry Organic Chemistry General Medicine molecular docking virtual screening SLP76 molecular dynamics 3. Good health Computer Science Applications Molecular Docking Simulation lcsh:Biology (General) lcsh:QD1-999 [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology 030220 oncology & carcinogenesis [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Ritonavir Pharmacophore Peptides Protein Binding medicine.drug |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, MDPI, 2019, 20 (19), pp.E4721. ⟨10.3390/ijms20194721⟩ International Journal of Molecular Sciences, 2019, 20 (19), pp.E4721. ⟨10.3390/ijms20194721⟩ Volume 20 Issue 19 International Journal of Molecular Sciences, Vol 20, Iss 19, p 4721 (2019) |
| ISSN: | 1661-6596 1422-0067 |
| DOI: | 10.3390/ijms20194721⟩ |
| Popis: | The enzyme phospholipase C gamma 1 (PLC&gamma 1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLC&gamma 1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLC&gamma 1 and its known binding partners. Indeed, molecular modeling of PLC&gamma 1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLC&gamma 1 and a comparable or higher binding affinity to ritonavir (∆Gbind < &minus 25 kcal/mol), one of the most potent inhibitor reported till now. |
| Databáze: | OpenAIRE |
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