Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction
Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction
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DOI：
10.1016/s1093-3263(03)00153-0
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发表时间：
2003-11-01
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;Shelver, WH
由于锌的多重配位几何形状以及缺乏适当的力场参数来模拟金属/配体相互作用，金属蛋白酶抑制剂的对接仍然是一个挑战。在本研究中，我们探讨了使用 AutoDock 3.0 进行基质金属蛋白酶 (MMP) 抑制剂对接的对接准确性和评分可靠性。通过将 16 种基质金属蛋白酶配体与其晶体结构对接来研究与锌离子相关的潜在问题。锌结合基团（ZBG）和锌之间的良好配位被证明是配体适合结合位点的先决条件。利用具有良好对接的 14 个 MMP 复合物对锌参数（包括锌半径、井深和锌电荷）进行了单纯形优化。使用优化的锌参数（锌半径：0.87 埃；井深：0.35 kcal/mol；锌电荷：+0.95 e）显示锌结合位点的对接精度和结合蛋白自由能的预测均得到改善。尽管需要进一步改进对接程序，特别是评分功能，但锌参数的优化提供了提高 AutoDock 作为药物发现工具性能的有效方法。 (C) 2003 Elsevier Inc. 保留所有权利。
Docking of metalloproteinase inhibitors remains a challenge due to the zinc multiple coordination geometries and the lack of appropriate force field parameters to model the metal/ligand interactions. In this study, we explore the docking accuracy and scoring reliability for the docking of matrix metalloproteinase (MMP) inhibitors using AutoDock 3.0. Potential problems associated with zinc ion were investigated by docking 16 matrix metalloproteinase ligands to their crystal structures. A good coordination between the zinc binding group (ZBG) and the zinc was shown to be a prerequisite for the ligand to fit the binding site. A simplex optimization of zinc parameters, including zinc radius, well depth, and zinc charges, was performed utilizing the 14 MMP complexes with good docking. The use of optimized zinc parameters (zinc radius: 0.87 Angstrom; well depth: 0.35 kcal/mol; and zinc charges: +0.95 e) shows improvement in both docking accuracy at the zinc binding site and the prediction of bindin free energies. Although further improvement in the docking procedure, particularly the scoring function is needed, optimization of zinc parameters provides an efficient way to improve the performance of AutoDock as a drug discovery tool. (C) 2003 Elsevier Inc. All rights reserved.