期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/ijms20194721
关键词
phospholipase C gamma 1; SLP76; virtual screening; pharmacophore mapping; molecular docking; molecular dynamics
资金
- Institut National Contre le Cancer (INCA)
- Region Pays de la Loire
- Centre national de la recherche scientifique (CNRS)
- INCa PLBIO-2018
- Ligue contre le cancer equipe labellisee 2016-2019
- Fondation ARC 2017-2019
- [ANR-17-CE15-0027]
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 (G(bind) < -25 kcal/mol), one of the most potent inhibitor reported till now.
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