Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor

[Image: see text] 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Weiss, Dahlia R., Ahn, SeungKirl, Sassano, Maria F., Kleist, Andrew, Zhu, Xiao, Strachan, Ryan, Roth, Bryan L., Lefkowitz, Robert J., Shoichet, Brian K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2013
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658555/
https://www.ncbi.nlm.nih.gov/pubmed/23485065
http://dx.doi.org/10.1021/cb400103f
_version_ 1782270294706094080
author Weiss, Dahlia R.
Ahn, SeungKirl
Sassano, Maria F.
Kleist, Andrew
Zhu, Xiao
Strachan, Ryan
Roth, Bryan L.
Lefkowitz, Robert J.
Shoichet, Brian K.
author_facet Weiss, Dahlia R.
Ahn, SeungKirl
Sassano, Maria F.
Kleist, Andrew
Zhu, Xiao
Strachan, Ryan
Roth, Bryan L.
Lefkowitz, Robert J.
Shoichet, Brian K.
author_sort Weiss, Dahlia R.
collection PubMed
description [Image: see text] 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.
format Online
Article
Text
id pubmed-3658555
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-36585552013-05-22 Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor Weiss, Dahlia R. Ahn, SeungKirl Sassano, Maria F. Kleist, Andrew Zhu, Xiao Strachan, Ryan Roth, Bryan L. Lefkowitz, Robert J. Shoichet, Brian K. ACS Chem Biol [Image: see text] 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. American Chemical Society 2013-03-13 2013-05-17 /pmc/articles/PMC3658555/ /pubmed/23485065 http://dx.doi.org/10.1021/cb400103f Text en Copyright © 2013 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Weiss, Dahlia R.
Ahn, SeungKirl
Sassano, Maria F.
Kleist, Andrew
Zhu, Xiao
Strachan, Ryan
Roth, Bryan L.
Lefkowitz, Robert J.
Shoichet, Brian K.
Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title_full Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title_fullStr Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title_full_unstemmed Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title_short Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor
title_sort conformation guides molecular efficacy in docking screens of activated β-2 adrenergic g protein coupled receptor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658555/
https://www.ncbi.nlm.nih.gov/pubmed/23485065
http://dx.doi.org/10.1021/cb400103f
work_keys_str_mv AT weissdahliar conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT ahnseungkirl conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT sassanomariaf conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT kleistandrew conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT zhuxiao conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT strachanryan conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT rothbryanl conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT lefkowitzrobertj conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor
AT shoichetbriank conformationguidesmolecularefficacyindockingscreensofactivatedb2adrenergicgproteincoupledreceptor