Modelling and receptor-based virtual screening studies of GPR139

Abstract

GPR139 belongs to Class A of GPCRs family and plays key role in molecular signalling through activation of receptors and promotes exchange of Guanosine Di-phosphate (GDP) to Guanosine Tri-phosphate (GTP). GPR139 is specifically involved in neuropeptide signalling pathway, phospholipase C-activating G-protein-coupled receptor signalling pathway and is coupled to IP3 second messenger (phospholipase C activating). In this article, we report 3D structure prediction of GPR139 using threading and ab initio methods. The models were validated and optimised. Molecular dynamics simulation of GPR139 was performed for 300 ns to investigate the dynamic perturbations in predicted model, particularly variations in seven transmembrane domains and active site residues. The active site residues were identified and the 3D model was screened against large databases of chemical libraries for identification of potential lead compounds which could bind to GPR139 receptor and activate signal transduction. The screened compounds were further refined through free binding energy calculations (ΔGbind) using generalised born and surface area continuum solvation for estimating ligand-binding affinities to GPR139.