Knegtel R M, Bayada D M, Engh R A, von der Saal W, van Geerestein V J, Grootenhuis P D
Department of Molecular Design and Informatics, N.V. Organon, The Netherlands.
J Comput Aided Mol Des. 1999 Mar;13(2):167-83. doi: 10.1023/a:1008014604433.
A set of 32 known thrombin inhibitors representing different chemical classes has been used to evaluate the performance of two implementations of incremental construction algorithms for flexible molecular docking: DOCK 4.0 and FlexX 1.5. Both docking tools are able to dock 10-35% of our test set within 2 A of their known, bound conformations using default sampling and scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant improvement over rigid body docking of single, rule-based conformations, which is still often used for docking of large databases. Docking of sets of multiple conformers of each inhibitor, obtained with a novel protocol for diverse conformer generation and selection, yielded results comparable to those obtained by flexible docking. Chemical scoring, which is an empirically modified force field scoring method implemented in DOCK 4.0, outperforms both interaction energy scoring by DOCK and the Böhm scoring function used by FlexX in rigid and flexible docking of thrombin inhibitors. Our results indicate that for reliable docking of flexible ligands the selection of anchor fragments, conformational sampling and currently available scoring methods still require improvement.
一组代表不同化学类别的32种已知凝血酶抑制剂已被用于评估用于柔性分子对接的增量构建算法的两种实现方式的性能：DOCK 4.0和FlexX 1.5。使用默认的采样和评分参数，两种对接工具都能够将我们测试集中10% - 35%的分子对接至其已知结合构象的2埃范围内。尽管使用DOCK或FlexX进行柔性对接无法重建所有天然复合物，但与仍然常用于大型数据库对接的基于单一规则构象的刚体对接相比，它确实有显著改进。使用一种用于多样构象生成和选择的新方案获得每种抑制剂的多个构象集进行对接，产生的结果与柔性对接获得的结果相当。化学评分是DOCK 4.0中实施的一种经经验修正的力场评分方法，在凝血酶抑制剂的刚体和柔性对接中，其性能优于DOCK的相互作用能评分和FlexX使用的Böhm评分函数。我们的结果表明，对于柔性配体的可靠对接，锚定片段的选择、构象采样和目前可用的评分方法仍需改进。
