Quantum chemistry study on the interaction of the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases
Quantum chemistry study on the interaction of the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases
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DOI：
10.1021/jp013336j
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发表时间：
2002-05-02
影响因子：
3.3
通讯作者：
Jiang, HL
中科院分区：
文献类型：
--
作者：
Cheng, F;Zhang, RH;Jiang, HL
采用密度泛函理论（DFT）B3 LYP/6- 31 G * 方法研究了6种锌配合物Zn（imidazole）（3）X（其中X =水、CH 3S-、异羟肟酸根、甲酰羟胺、次磷酸根和乙酸根）与基质金属蛋白酶（MMP）中锌离子的相互作用.根据我们的计算，它们的相互作用模式可以分为三类。这些配合物的结构特征与剑桥结构数据库和蛋白质数据库中的X射线数据一致。原子电荷分析表明，金属基质蛋白酶活性中心的催化水分子与锌离子配位后被激活，成为一种良好的亲核试剂，攻击并降解基质蛋白酶的底物。这些配合物的几何参数，电荷转移从外源配体的Zn（II），和计算的相对结合自由能表征这些配体与锌离子的结合能力。的MMP抑制剂，其中含有相同的取代基和不同的锌结合基团（ZBG）的抑制活性，以及与DFT计算预测的结合自由能与相关系数为0.969的matrilysin和0.939的人成纤维细胞胶原酶（HFC）。这为预测新设计的MMP抑制剂的抑制活性提供了一种可能的良好策略;因此，使用这种范例将表现出ZBG与Zn（II）的强结合能力的那些潜在抑制剂将预期具有更大的抑制活性。
Six zinc complexes, Zn(imidazole)(3)X (where X = water, CH3S-, hydroxamate, formylhydroxylamine, hypophosphite, and acetate), have been calculated with the density functional theory (DFT) method B3LYP/6-31G* to probe the interaction between the exogenous ligands and the catalytic zinc ion in matrix metalloproteinases (MMPs). According to our calculation, their interaction modes can be divided into three classes. The structural features of these complexes are in agreement with the X-ray data in the Cambridge Structural Database and the Protein Data Bank. The atomic charge analyses proved that the catalytic water molecule in the active site of MMPs can be activated after coordinating with the zinc ion and thus acts as a good nucleophile to attack and degrade the substrate of MMPs. The geometric parameters of these complexes, the charge transfers from the exogenous ligands to the Zn(II), and the calculated relative binding, free energy characterize well the binding ability of these ligands with the zinc ion. The inhibitory activities of the MMP inhibitors, which contain the same substituents and different zinc binding groups (ZBGs), correlate well with the binding free energies predicted by the DFT calculation with correlation coefficients of 0.969 for matrilysin and 0.939 for human fibroblast collagenase (HFC). This gives a possible good strategy for predicting the inhibitory activity for the newly designed inhibitors of MMPs; those potential inhibitors that would exhibit strong binding ability of ZBGs to Zn(II) using this paradigm would therefore be expected to have greater inhibitory activity.