title: Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158-2550, USA.
authors.forename: Dahlia R
authors.initials: DR
authors.lastname: Weiss
authors.forename: SeungKirl
authors.initials: S
authors.lastname: Ahn
authors.forename: Maria F
authors.initials: MF
authors.lastname: Sassano
authors.forename: Andrew
authors.initials: A
authors.lastname: Kleist
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Ryan
authors.initials: R
authors.lastname: Strachan
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D048588:Benzoxazines; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D054852:Small Molecule Libraries; D040681:Structural Homology, Protein
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C584569:BI167107; D048588:Benzoxazines; D004983:Ethanolamines; D008024:Ligands; D009025:Morpholines; D018343:Receptors, Adrenergic, beta-2; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D000242:Cyclic AMP