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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Weiss, DR; Ahn, S; Sassano, MF; Kleist, A; Zhu, X; Strachan, R; Roth, BL; Lefkowitz, RJ; Shoichet, BK

Published Date

  • May 17, 2013

Published In

Volume / Issue

  • 8 / 5

Start / End Page

  • 1018 - 1026

PubMed ID

  • 23485065

Pubmed Central ID

  • PMC3658555

Electronic International Standard Serial Number (EISSN)

  • 1554-8937

Digital Object Identifier (DOI)

  • 10.1021/cb400103f


  • eng

Conference Location

  • United States