Virtual screening of biogenic amine-binding G-protein coupled receptors: Comparative evaluation of protein- and ligand-based virtual screening protocols
Virtual screening of biogenic amine-binding G-protein coupled receptors: Comparative evaluation of protein- and ligand-based virtual screening protocols
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DOI：
10.1021/jm050090o
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发表时间：
2005-08-25
影响因子：
7.3
通讯作者：
Klabunde, T
中科院分区：
文献类型：
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作者：
Evers, A;Hessler, G;Klabunde, T
在本文中，我们比较了基于蛋白质和基于配体的虚拟筛选技术来鉴定四种生物胺结合g蛋白偶联受体（gpcr）的配体。为了筛选虚拟化合物文库，我们使用了(1)与GPCR同源性模型的分子对接，(2)基于配体的药效团和特征树模型，(3)三维（3D）相似性搜索，以及(4)基于二维（2D）分子描述符的统计方法[偏最小二乘（PLS）和偏最小二乘判别分析（PLS- da）模型]。从虚拟文库中检索已知拮抗剂的不同方法的比较表明，在我们的研究中，基于配体的药效团、特征树和基于二维定量构效关系（QSAR）的筛选技术提供的富集因子高于分子对接到GPCR同源模型所提供的富集因子。尽管如此，当与GOLD对接并使用GoldScore对配体进行排名时（在筛选的数据库中排名前1%的配体中高达60%）取得的命中率仍然令人满意。这些结果表明，对接到GPCR同源性模型可以是一个有用的方法，通过虚拟筛选发现铅时，无论是很少或没有信息的活性配体可用。
In this paper, we compare protein- and ligand-based virtual screening techniques for identifying the ligands of four biogenic amine-binding G-protein coupled receptors (GPCRs). For the screening of the virtual compound libraries, we used (1) molecular docking into GPCR homology models, (2) ligand-based pharmacophore and Feature Tree models, (3) three-dimensional (3D)similarity searches, and (4) statistical methods [partial least squares (PLS) and partial least squares discriminant analysis (PLS-DA) models] based on two-dimensional (2D) molecular descriptors. The comparison of the different methods in retrieving known antagonists from virtual libraries shows that in our study the ligand-based pharmacophore-, Feature Tree-, and 2D quantitative structure-activity relationship (QSAR)-based screening techniques provide enrichment factors that are higher than those provided by molecular docking into the GPCR homology models. Nevertheless, the hit rates achieved when docking with GOLD and ranking the ligands with GoldScore (up to 60% among the top-ranked 1% of the screened databases) are still satisfying. These results suggest that docking into GPCR homology models can be a useful approach for lead finding by virtual screening when either little or no information about the active ligands is available.