Efficiency of Homology Modeling Assisted Molecular Docking in G-protein Coupled Receptors.

Background: Molecular docking is in regular practice to assess ligand affinity on a target protein crystal structure. In the absence of protein crystal structure, the homology modeling or comparative modeling is the best alternative to elucidate the relationship details between a ligand and protein at the molecular level. The development of accurate homology modeling (HM) and its integration with molecular docking (MD) is essential for successful, rational drug discovery.

Objective: The G-protein coupled receptors (GPCRs) are attractive therapeutic targets due to their immense role in human pharmacology. The GPCRs are membrane-bound proteins with the complex constitution, and the understanding of their activation and inactivation mechanisms is quite challenging. Over the past decade, there has been a rapid expansion in the number of solved G-protein-coupled receptor (GPCR) crystal structures; however, the majority of the GPCR structures remain unsolved. In this context, HM guided MD has been widely used for structure-based drug design (SBDD) of GPCRs.

Methods: The focus of this review is on the recent (i) developments on HM supported GPCR drug discovery in the absence of GPCR crystal structures and (ii) application of HM in understanding the ligand interactions at the binding site, virtual screening, determining receptor subtype selectivity and receptor behaviour in comparison with GPCR crystal structures.

Results: The HM in GPCRs has been extremely challenging due to the scarcity in template structures. In such a scenario, it is difficult to get accurate HM that can facilitate understanding of the ligand-receptor interactions. This problem has been alleviated to some extent by developing refined HM based on incorporating active /inactive ligand information and inducing protein flexibility. In some cases, HM proteins were found to outscore crystal structures.

Conclusion: The developments in HM have been highly operative to gain insights about the ligand interaction at the binding site and receptor functioning at the molecular level. Thus, HM guided molecular docking may be useful for rational drug discovery for the GPCRs mediated diseases.