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 thesearch of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed insquamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 washere modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structurewas further validated by comparison with structural features of the templates through Verify-3D, ProSA andERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandranplot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation andsolvation of protein were studied through explicit spherical boundaries with a harmonic restraint membranewater system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, whereGPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silicomodification of some substrate ligands was carried out to form polar interactions with A