Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex.
Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex.
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DOI：
10.1021/ci900031y
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发表时间：
2009-06
影响因子：
5.6
通讯作者：
Tjarks W
中科院分区：
文献类型：
--
作者：
Tiwari R;Mahasenan K;Pavlovicz R;Li C;Tjarks W
含有硼原子的化合物在各种疾病，特别是癌症的治疗和诊断中发挥着越来越重要的作用。然而，含硼治疗和诊断的计算药物设计受到以下事实的阻碍：许多用于此目的的软件包缺乏各种类型硼原子的全部或部分参数。在本文中，我们描述了克服该问题的简单而有效的策略，该策略基于用碳原子类型替换硼原子类型。通过使用 AutoDock、Glide、FlexX 和 Surflex 将 closo- 和 nido-carboranyl 抗叶酸剂对接至人二氢叶酸还原酶 (hDHFR) 的活性位点，并将获得的对接姿势与原始 hDHFR-carboranyl 抗叶酸剂晶体结构中对应物的姿势进行比较，对所开发的方法进行了验证。在优化条件下，AutoDock 和 Glide 在对接 closo-carboranyl 抗叶酸剂、随后 Surflex 和 FlexX 方面同样出色，而 Autodock、Glide 和 Surflex 被证明在对接 nido-carboranyl 抗叶酸剂、随后 FlexX 方面相当有效。由不同数据源和/或优化方法导致的碳硼烷基抗叶酸剂结构中几何形状和部分原子电荷的差异并未显着影响 AutoDock 或 Glide 的对接性能。所有四个程序生成的评分函数均符合实验数据。
Compounds containing boron atoms play increasingly important roles in the therapy and diagnosis of various diseases, particularly cancer. However, computational drug design of boron-containing therapeutics and diagnostics is hampered by the fact that many software packages used for this purpose lack parameters for all or part of the various types of boron atoms. In the present paper, we describe simple and efficient strategies to overcome this problem, which are based on the replacement of the boron atom types with carbon atom types. The developed methods were validated by docking closo- and nido-carboranyl antifolates into the active site of a human dihydrofolate reductase (hDHFR) using AutoDock, Glide, FlexX, and Surflex and comparing the obtained docking poses with the poses of their counterparts in the original hDHFR-carboranyl antifolate crystal structures. Under optimized conditions, AutoDock and Glide were equally good in docking of the closo-carboranyl antifolates followed by Surflex and FlexX whereas Autodock, Glide, and Surflex proved to be comparably efficient in the docking of nido-carboranyl antifolates followed by FlexX. Differences in geometries and partial atom charges in the structures of the carboranyl antifolates resulting from different data sources and/or optimization methods did not impact the docking performances of AutoDock or Glide significantly. Scoring functions generated by all four programs were in accordance with experimental data.
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