Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design

Abstract

The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.

Natural flavonoid pectolinarin computationally targeted as a promising drug candidate against SARS-CoV-2

“…The 3D modelled structure of SARS-CoV-2 and SARS-CoV were built by using as template the prefusion structure of SARS-CoV spike glycoprotein, conformation 2 (PDBID: 5 × 5B) ( Yuan et al, 2017 ) and SARS-CoV complex with human neutralizing S230 antibody Fab fragment (PDBID: 6NB6 ) ( Walls et al, 2019 ) with a sequence identity 64% and 84% respectively. The criteria for selection of the best 3Dstructures were predicted by using PDB advance BLAST analysis and the structures used in further analysis were those showing extreme score and query coverage ( Rani et al, 2013 ). The homology of SARS-CoV-2 and SARS-CoV structures and their comparison are listed in Supplementary Table 1 .…”