Park Min-Sun, Dessal Axel L, Smrcka Alan V, Stern Harry A
Departments of Biochemistry and Biophysics, University of Rochester, Rochester, New York 14627, USA.
J Chem Inf Model. 2009 Feb;49(2):437-43. doi: 10.1021/ci800384q.
Several studies have suggested that disrupting interactions of the G protein betagamma subunits with downstream binding partners might be a valuable study for pharmaceutical development. Recently, small molecules have been found which bind to Gbetagamma with high apparent affinity in an enzyme-linked immunosorbent assay (ELISA), have demonstrated selective inhibition of interactions of Gbetagamma with downstream signaling partners, and have been shown to increase antinociceptive effects of morphine and inhibit inflammation in vivo. In this paper we examine several docking and scoring protocols for estimating binding affinities for a set of 830 ligands from the NCI diversity set to the Gbeta1gamma2 subunit and compared these with IC50s measured in a competition ELISA with a high-affinity peptidic ligand. The best-performing docking protocol used a consensus score and ensemble docking and resulted in a 6-fold enrichment of high-affinity compounds in the top-ranked 5% of the ligand data set.
多项研究表明，破坏G蛋白βγ亚基与下游结合伴侣的相互作用可能是药物研发的一个有价值的研究方向。最近，人们发现了一些小分子，它们在酶联免疫吸附测定（ELISA）中以高表观亲和力与Gβγ结合，已证明能选择性抑制Gβγ与下游信号伴侣的相互作用，并且已显示出可增强吗啡的镇痛作用并在体内抑制炎症。在本文中，我们研究了几种对接和评分方案，以估计来自美国国立癌症研究所（NCI）多样性集的830种配体与Gβ1γ2亚基的结合亲和力，并将这些结果与在与高亲和力肽配体的竞争ELISA中测得的IC50值进行比较。表现最佳的对接方案使用了一致性评分和整体对接，在配体数据集排名前5%的化合物中，高亲和力化合物的富集倍数达到了6倍。
