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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / chemistry
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Benzoxazines
  • Binding Sites
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Drug Evaluation, Preclinical / methods*
  • Ethanolamines / chemistry
  • Ethanolamines / pharmacology
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Docking Simulation
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Protein Conformation
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Receptors, Dopamine D2 / chemistry
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry
  • Small Molecule Libraries
  • Structural Homology, Protein

Substances

  • Adrenergic beta-2 Receptor Agonists
  • BI167107
  • Benzoxazines
  • Ethanolamines
  • Ligands
  • Morpholines
  • Receptors, Adrenergic, beta-2
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • Cyclic AMP