MOLECULAR RECOGNITION OF THE INHIBITOR AG-1343 BY HIV-1 PROTEASE - CONFORMATIONALLY FLEXIBLE DOCKING BY EVOLUTIONARY PROGRAMMING
MOLECULAR RECOGNITION OF THE INHIBITOR AG-1343 BY HIV-1 PROTEASE - CONFORMATIONALLY FLEXIBLE DOCKING BY EVOLUTIONARY PROGRAMMING
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DOI：
10.1016/1074-5521(95)90050-0
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发表时间：
1995-05-01
影响因子：
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通讯作者：
FREER, ST
中科院分区：
文献类型：
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作者：
GEHLHAAR, DK;VERKHIVKER, GM;FREER, ST
背景资料：基于计算结构的药物设计的一个重要先决条件是预测配体-蛋白质复合物的结构，这些结构尚未通过X射线晶体学或NMR实验确定。对于这项任务，刚性配体的对接是不够的，因为它假设的知识结合配体的构象。柔性配体的对接将是期望的，但需要搜索巨大的构象空间。我们着手开发一种灵活的对接策略，结合一个简单的模型配体-蛋白质相互作用的分子recognition与进化规划search technique.Results：我们已经开发出一个分子间的能量函数，结合空间位阻和氢键项。该函数中的参数是通过在三种不同蛋白质体系中进行对接获得的。该方法的有效性被证明通过构象柔性对接的抑制剂AG-1343，一个潜在的新的抗艾滋病药物，到HIV-1蛋白酶。对于这种具有九个可旋转键的分子，在100次模拟中，晶体结构在1.5埃均方根偏差内再现了34次，每次需要在Silicon Graphics R4400工作站上花费8分钟。能量函数正确评估的晶体结构作为全球能源minimum.Conclusions：我们认为，对接问题的解决方案可以通过匹配一个简单的模型，一个有效的搜索程序的分子识别来实现。分子识别模型的必要成分仅包括空间和氢键相互作用项。虽然这些术语不一定足以预测结合亲和力，但它们忠实地描述了配体-蛋白质相互作用，足以使对接程序能够预测结合配体的结构。因此，这种对接策略为合理药物设计的跨学科领域提供了重要工具。
Background: An important prerequisite for computational structure-based drug design is prediction of the structures of ligand-protein complexes that have not yet been experimentally determined by X-ray crystallography or NMR. For this task, docking of rigid ligands is inadequate because it assumes knowledge of the conformation of the bound Ligand. Docking of flexible ligands would be desirable, but requires one to search an enormous conformational space. We set out to develop a strategy for flexible docking by, combining a simple model of ligand-protein interactions for molecular recognition with an evolutionary programming search technique.Results: We have developed an intermolecular energy function that incorporates steric and hydrogen-bonding terms. The parameters in this function were obtained by docking in three different protein systems. The effectiveness of this method was demonstrated by conformationally flexible docking of the inhibitor AG-1343, a potential new drug against AIDS, into HIV-1 protease. For this molecule, which has nine rotatable bonds, the crystal structure was reproduced within 1.5 Angstrom root-mean-square deviation 34 times in 100 simulations, each requiring eight minutes on a Silicon Graphics R4400 workstation. The energy function correctly evaluates the crystal structure as the global energy minimum.Conclusions: We believe that a solution of the docking problem may be achieved by matching a simple model of molecular recognition with an efficient search procedure. The necessary ingredients of a molecular recognition model include only steric and hydrogen-bond interaction terms. Although these terms are not necessarily sufficient to predict binding affinity, they describe ligand-protein interactions faithfully enough to enable a docking program to predict the structure of the bound ligand. This docking strategy thus provides an important tool for the interdisciplinary field of rational drug design.