Rational automatic search method for stable docking models of protein and ligand.
Rational automatic search method for stable docking models of protein and ligand.
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DOI：
10.1006/jmbi.1994.1656
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发表时间：
1994-10
影响因子：
5.6
通讯作者：
M. Mizutani;N. Tomioka;A. Itai
中科院分区：
文献类型：
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作者：
M. Mizutani;N. Tomioka;A. Itai
已经开发出一种有效的自动方法将配体分子与蛋白质分子对接。考虑到两个分子之间的特定相互作用和配体的构象灵活性，该方法可以构建积极有利的对接模型。在对接的第一阶段，根据氢键以及包括氢键基团的部分配体结构中的构象来有效地搜索和估计可能的结合模式。当该部分被放置在蛋白质空腔中并被优化后，剩余部分的构象也被系统地检查。最后，通过对整个配体分子的位置、方向和构象的优化，得到了几种稳定的对接模型。在所有筛选过程中，均以包括分子内和分子间相互作用能（由范德华力、静电力和氢键能）组成的总势能作为指标。我们的对接方法的特点是结果精度高、模型全自动生成、计算时间短。使用两种酶系统的四次对接试验证实了该方法的效率。在将甲氨蝶呤与二氢叶酸还原酶对接以及将 2'-GMP 与核糖核酸酶 T1 对接的两次尝试中，晶体中复合物的精确结构被再现为最稳定的对接模型，而没有任何关于结合模式和配体构象的假设。二氢叶酸和甲氧苄啶分别与二氢叶酸还原酶最稳定的对接模型也与实验结果吻合良好。在所有测试案例中，结果表明我们的方法可以准确预测正确的对接结构，区分正确的模型和错误的模型。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的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的药物设计和生化反应机制的研究提供了有用的工具。
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.