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

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• 作者：Dahlia R. Weiss ; SeungKirl Ahn ; Maria F. Sassano ; Andrew Kleist ; Xiao Zhu ; Ryan Strachan ; Bryan L. Roth ; Robert J. Lefkowitz ; Brian K. Shoichet
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：May 17, 2013
• 年：2013
• 卷：8
• 期：5
• 页码：1018-1026
• 全文大小：441K
• 年卷期：v.8,no.5(May 17, 2013)
• ISSN：1554-8937

文摘

A prospective, large library virtual screen against an activated 尾2-adrenergic receptor (尾2AR) 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 尾2AR structure returned few hits of only marginal potency.