Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158-2550, USA.
ACS Chem Biol. 2013 May 17;8(5):1018-26. doi: 10.1021/cb400103f. Epub 2013 Mar 21.
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.
一项针对激活的β2-肾上腺素能受体（β2AR）结构的前瞻性大型文库虚拟筛选，排除了反向激动剂，仅返回了强效激动剂，为之前针对与反向激动剂结合的 G 蛋白偶联受体（GPCR）结构的虚拟筛选提供了第一个补充，这些筛选仅预测了反向激动剂。此外，有两个命中物再现了与 G 蛋白和阻滞蛋白介导的信号转导相关的共结晶配体的信号转导特征。这种功能保真度在药物设计中具有重要意义，因为能够预测具有预定义信号特性的配体是非常理想的。然而，激动剂结合状态为建模其他 GPCR 的激活构象提供了一个不确定的模板，因为基于激活的β2AR 结构模板化的多巴胺 D2 受体（DRD2）激活模型返回的命中物数量很少，且效力也很有限。
