Mizutani M Y, Tomioka N, Itai A
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Mol Biol. 1994 Oct 21;243(2):310-26. doi: 10.1006/jmbi.1994.1656.
An efficient automatic method has been developed for docking a ligand molecule to a protein molecule. The method can construct energetically favorable docking models, considering specific interactions between the two molecules and conformational flexibility in the ligand. In the first stage of docking, likely binding modes are searched and estimated effectively in terms of hydrogen bonds, together with conformations in part of the ligand structure that includes hydrogen bonding groups. After that part is placed in the protein cavity and is optimized, conformations in the remaining part are also examined systematically. Finally, several stable docking models are obtained after optimization of the position, orientation and conformation of the whole ligand molecule. In all the screening processes, the total potential energy including intra- and intermolecular interaction energy, consisting of van der Waals, electrostatic and hydrogen bonding energies, is used as the index. The characteristics of our docking method are high accuracy of the results, fully automatic generation of models and short computational time. The efficiency of the method was confirmed by four docking trials using two enzyme systems. In two attempts to dock methotrexate to dihydrofolate reductase and 2'-GMP to ribonuclease T1, the exact structures of complexes in crystals were reproduced as the most stable docking models, without any assumptions concerning the binding modes and ligand conformations. The most stable docking models of dihydrofolate and trimethoprim, respectively, to dihydrofolate reductase were also in good agreement with those suggested by experiment. In all test cases, it was shown that our method can accurately predict the correct docking structures, discriminating the correct model from incorrect ones. The efficiency of our method was further tested from the viewpoint of ability to predict the relative stability of the docking structures of two triazine derivatives to dihydrofolate reductase. Our docking method provides a useful tool for rational drug design and investigations of biochemical reaction mechanisms.
已开发出一种高效的自动方法，用于将配体分子与蛋白质分子对接。该方法能够构建能量上有利的对接模型，同时考虑两个分子之间的特定相互作用以及配体中的构象灵活性。在对接的第一阶段，根据氢键有效地搜索和估计可能的结合模式，以及配体结构中包括氢键基团的部分的构象。将该部分放置在蛋白质腔中并进行优化后，还会系统地检查其余部分的构象。最后，在对整个配体分子的位置、取向和构象进行优化后，获得了几个稳定的对接模型。在所有筛选过程中，包括分子内和分子间相互作用能的总势能（由范德华能、静电能和氢键能组成）用作指标。我们对接方法的特点是结果准确性高、模型完全自动生成且计算时间短。该方法的效率通过使用两个酶系统的四次对接试验得到了证实。在两次将甲氨蝶呤对接至二氢叶酸还原酶以及将2'-鸟苷酸对接至核糖核酸酶T1的尝试中，晶体中复合物的确切结构被重现为最稳定的对接模型，无需对结合模式和配体构象做任何假设。二氢叶酸和甲氧苄啶分别与二氢叶酸还原酶的最稳定对接模型也与实验结果相符。在所有测试案例中，结果表明我们的方法能够准确预测正确的对接结构，区分正确模型与错误模型。我们还从预测两种三嗪衍生物与二氢叶酸还原酶对接结构的相对稳定性的能力角度，进一步测试了我们方法的效率。我们的对接方法为合理药物设计和生化反应机制研究提供了一个有用的工具。
