Fragment-based flexible ligand docking by evolutionary optimization
Fragment-based flexible ligand docking by evolutionary optimization
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DOI：
10.1515/bc.2001.168
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发表时间：
2001-09-01
影响因子：
3.7
通讯作者：
Caflisch, A
中科院分区：
文献类型：
--
作者：
Budin, N;Majeux, N;Caflisch, A
提出了一种新的计算方法，用于柔性配体在刚性蛋白质中的有效对接。它利用了结合模式的功能团确定了一个详尽的搜索与溶剂化。在配体构象空间的搜索是由遗传算法，其评分函数近似的空间位阻效应和分子间氢键。遗传算法生成的配体构象通过优化其片段与化学相关官能团的最佳位置的拟合而停靠在蛋白质结合位点中。我们表明，使用最佳的结合模式的分子片段允许对接已知的抑制剂与约10个可旋转的键在活性位点的凝血酶和HIV-1蛋白酶的未复合和复合构象。
A new computational approach for the efficient docking of flexible ligands in a rigid protein is presented. It exploits the binding modes of functional groups determined by an exhaustive search with solvation. The search in ligand conformational space is performed by a genetic algorithm whose scoring function approximates steric effects and intermolecular hydrogen bonds. Ligand conformations generated by the genetic algorithm are docked in the protein binding site by optimizing the fit of their fragments to optimal positions of chemically related functional groups. We show that the use of optimal binding modes of molecular fragments allows to dock known inhibitors with about ten rotatable bonds in the active site of the uncomplexed and complexed conformations of thrombin and HIV-1 protease.