Recent advances in structure-based virtual screening of G-protein coupled receptors

Abstract

In addition to the rhodopsin crystal structure, high-resolution crystal structures of ligand-mediated G-protein-coupled receptors (GPCRs) have recently become available, and these have become attractive templates for developing homology models of several GPCRs of therapeutic interest. These crystal structures and the homology models derived from them have provided significant insights into ligand-receptor interactions. Moreover, several studies have demonstrated that the structural models are indeed suitable for virtual screening of compound databases to identify new ligands for various GPCRs. Recent examples of such virtual screening against GPCRs are discussed in this review.

Fig. 1

Crystal structures of retinal-bound rhodopsin (a, PDB id 1U19) and carazolol-bound β2-adrenergic receptor (b, PDB id 2RH1). The ligands retinal and carazolol are shown in ball and stick representation with carbon atoms colored brown, while the extracellular loops 2 (ECL2) are shown in yellow. In rhodopsin, ECL2 and the N terminus form a lid over the ligand-binding pocket, whereas in β2-adrenergic receptor the ECL2 contains an extrahelical segment and is more exposed to the solvent, giving open access to the ligand-binding pocket

Fig. 2

Structures of carazolol, carvedilol, and related ligands predicted to bind like carazolol to β2 adrenergic receptor

Fig. 3

Structures of human histamine H4 receptor identified by virtual screening

Fig. 4

Structures of salvinorin A and related compounds used in pharmacophore modeling and docking at kappa opioid receptor

Fig. 5

Structures of antagonist ligands of melanin-concentrating hormone receptor 1 identified by virtual screening

Fig. 6

Structures of thyrotropin-releasing hormone receptor 1 antagonists identified by virtual screening

Fig. 7

Structures of agonist or partial agonist ligands of the free fatty acid receptor 1 identified by virtual screening

Fig. 8

Structures of compounds identified as inhibitors of photoactivated rohodopsin and transducin by virtual screening