Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You?

Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (β2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.

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Efficiency of Homology Modeling assisted Molecular Docking in G-protein coupled receptors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200908165250 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shome S. Bhunia ◽

Anil K. Saxena

Keyword(s):

Molecular Docking ◽

Drug Discovery ◽

Homology Modeling ◽

Crystal Structures ◽

G Protein ◽

G Protein Coupled Receptors ◽

Protein Crystal ◽

Protein Crystal Structure ◽

Rational Drug ◽

G Protein Coupled

Background: Molecular docking is in regular practice to assess ligand affinity on a target protein crystal structure. In 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 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 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 absence of GPCR crystal structures (ii) application of HM in understanding the ligand interactions at the binding site, virtual screening, determining receptor sub type 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 also. Conclusion: The developments in HM have been highly operative to gain insights about the ligand interaction at the binding site and receptor functioning at molecular level. Thus HM guided molecular docking may be useful for rational drug discovery for the GPCRs mediated diseases.

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