Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G-protein coupled receptor.

Authors: Weiss DR, Ahn S, Sassano MF, Kleist A, Zhu X, Strachan R, Roth BL, Lefkowitz RJ and Shoichet BK.
Publisher/Year: ACS Chem Biol 8(5):1018-26.
Pub Med ID/Journal ID: PMID:23485065

Abstract

A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.