Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries
Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries
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DOI：
10.1021/ci700044s
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Belew, Richard K.
中科院分区：
文献类型：
--
作者：
Chang, Max W.;Lindstrom, William;Belew, Richard K.
FightAIDS@Home分布式计算项目使用AutoDock对针对广泛的1771种配体的HIV蛋白酶结构进行初始虚拟筛选，其中包括已知的蛋白酶抑制剂和其他配体的多样化文库。大量的结果使得对HIV结构的结合能“分布”的新的大规模分析成为可能。除了识别潜在的先导化合物外，这些特征还提供了从更大的集合中选择具有代表性的野生型和突变蛋白质结构的方法。从PDB结构的结合能谱中，基于主成分分析的分析确定了七种跨越的蛋白水解酶。互补分析发现，野生型蛋白酶结构2BPZ最能捕捉到蛋白酶集合的中心趋势。使用已知的蛋白酶抑制剂与不同的配体集进行比较，在显著的、强结合的配体和其他弱/非特异性结合能之间产生-7.0kcal/mol的AutoDock结合能“显著”阈值。这个阈值捕获了近98%的已知抑制物相互作用，同时拒绝了超过95%的可疑非抑制物相互作用。这些方法应该在虚拟筛查项目中普遍使用，并将用于改进进一步的FightAIDS@Home实验。
The FightAIDS@Home distributed computing project uses AutoDock for an initial virtual screen of HIV protease structures against a broad range of 1771 ligands including both known protease inhibitors and a diverse library of other ligands. The volume of results allows novel large-scale analyses of binding energy "profiles" for HIV structures. Beyond identifying potential lead compounds, these characterizations provide methods for choosing representative wild-type and mutant protein structures from the larger set. From the binding energy profiles of the PDB structures, a principal component analysis based analysis identifies seven "spanning" proteases. A complementary analysis finds that the wild-type protease structure 2BPZ best captures the central tendency of the protease set. Using a comparison of known protease inhibitors against the diverse ligand set yields an AutoDock binding energy "significance" threshold of -7.0 kcal/mol between significant, strongly binding ligands and other weak/nonspecific binding energies. This threshold captures nearly 98% of known inhibitor interactions while rejecting more than 95% of suspected noninhibitor interactions. These methods should be of general use in virtual screening projects and will be used to improve further FightAIDS@Home experiments.