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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2013
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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 |
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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 |
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