期刊
FRONTIERS IN CHEMISTRY
卷 6, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2018.00023
关键词
GPR142; virtual screening; pharmacophore hypothesis; VSW; IFD; systems biology; MD simulation; type 2 diabetes mellitus (T2DM)
资金
- Ministry of Science and Technology of China [2016YFA0501703]
- State Key Lab on Microbial Metabolism
- Shanghai Jiao Tong University
- Center for High Performance Computing, Shanghai Jiao Tong University
GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to Class A of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.
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