The G-protein-coupled receptors are a part of the largest and most physiologically relevant family of membrane proteins. One-third of the medications, now on the market, target the GPCR receptor family, which is one of the most important therapeutic targets for many disorders. In the reported work, we have focussed on orphan GPR88 receptor which is a part of the GPCR protein family and a potential target for central nervous system disorders. GPR88 is known to show the highest expression in the striatum, which is a key region in motor control and cognitive functions. Recent studies have reported that GPR88 is activated by two agonists, 2-PCCA and RTI-13951-33. In this study, we have predicted the three-dimensional protein structure for the orphan GPR88 using the homology modeling approach. We then used shape-based screening techniques based on known agonists and structure-based virtual screening methods employing docking to uncover novel GPR88 ligands. The screened GPR88-ligand complexes were further subjected to molecular dynamics simulation studies. The selected ligands could fasten the development of novel treatments for the vast list of movement and central nervous system disorders.Communicated by Ramaswamy H. Sarma.
Keywords: GPCR; GPR88; central nervous system disorders; molecular docking; molecular dynamics simulation; virtual screening.