A practical approach to docking of zinc metalloproteinase inhibitors
A practical approach to docking of zinc metalloproteinase inhibitors
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DOI：
10.1016/j.jmgm.2003.11.002
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发表时间：
2004-03-01
影响因子：
2.9
通讯作者：
Shelver, WH
中科院分区：
文献类型：
--
作者：
Hu, X;Balaz, S;Shelver, WH
使用5种对接/评分方法(DOCK、FLEXX、DrugScore、GOLD和AutoDock)对40个已知晶体结构的锌依赖金属蛋白酶/配体复合体进行重新对接。配体的锌结合基团(ZBG)和催化锌之间配位键的正确几何构型对于对接的准确性和评分的可靠性是重要的。超过75%的对接姿势的RMSD小于2 Angstrom被发现具有适当的ZBG绑定，但对于较差的ZBG绑定，约95%的姿势无法正确对接。消除具有不适当锌结合的姿势导致更好的结合能预测，通过根据ZBG(羧酸盐、羟胺酸盐和含磷基团)将配体划分为子集而进一步改进。在使用针对单个子集获得的回归函数对子集进行重新评分后，DrugScore能够解释77%的结合能，共识评分方案X-CSCORE甚至能够解释88%的结合能差异。这种基于ZBG的姿势选择和子集重新评分相结合的方法将所有测试方法在金属蛋白酶抑制剂虚拟筛选中的命中率提高了4-16%。(C)2003 Elsevier Inc.保留所有权利。
Forty zinc-dependent metalloproteinase/ligand complexes with known crystal structures were re-docked using five docking/scoring approaches (DOCK, FlexX, DrugScore, GOLD, and AutoDock). Correct geometry of the coordination bonds between the ligand's zinc binding group (ZBG) and the catalytic zinc is important for docking accuracy and scoring reliability. More than 75% of docked poses with RMSD less than 2 Angstrom were found to have appropriate ZBG binding, but for poor ZBG binding, about 95% of poses failed to dock correctly. Elimination of poses with inappropriate zinc binding resulted in better binding energy predictions that were further improved by dividing the ligands into subsets according to the ZBG (carboxylates, hydroxamates, and phosphorus containing groups). After a subset re-scoring using the regression functions obtained for individual subsets, DrugScore was able to explain 77% and the consensus scoring scheme X-CSCORE even 88% of variance in binding energies. The approach combining ZBG-based pose selection and subset re-scoring improved the hit rate in virtual screening for metalloproteinase inhibitors for all tested methods by 4-16%. (C) 2003 Elsevier Inc. All rights reserved.