Structure-based drug screening for G-protein-coupled receptors

Abstract

G-protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets; however, progress in identifying new small molecule drugs has been disappointing. The past 4 years have seen remarkable progress in the structural biology of GPCRs, raising the possibility of applying structure-based approaches to GPCR drug discovery efforts. Of the various structure-based approaches that have been applied to soluble protein targets, such as proteases and kinases, in silico docking is among the most ready applicable to GPCRs. Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets. This review will focus on the current state of in silico docking for GPCRs.

Figure 1

New inverse agonists against the β₂AR structure discovered by molecular docking. Top row: four relatively potent ligands that resemble known chemotypes, with K_i values from 9 nM to 2 uM. Bottom row: two novel chemotypes, with K_i values of 1.1 and 3.3 uM.

Figure 2

Comparison of the binding pocket of the β₂AR in the inactive (carbons in blue) and active (carbons in orange) conformations. The inverse agonist carazolol is shown with carbons in green. The largest difference is observed around Ser207 in transmembrane segment (TM) 5.

Figure 3

A 9 nM inverse agonist of β₂AR discovered by docking: docked orientation (carbons in blue) superposed on the subsequent x-ray crystallographic result (carbons in green).[46]