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ACS Chem Biol. 2013 May 17;8(5):1018-26. doi: 10.1021/cb400103f. Epub 2013 Mar 21.

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

Author information

1
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158-2550, USA.

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.

PMID:
23485065
PMCID:
PMC3658555
DOI:
10.1021/cb400103f
[Indexed for MEDLINE]
Free PMC Article

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