Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
J Comput Chem. 2010 Jan 15;31(1):24-42. doi: 10.1002/jcc.21279.
Zinc-dependent matrix metalloproteinase (MMP) family is considered to be an attractive target because of its important role in many physiological and pathological processes. In the present work, a molecular modeling study combining protein-, ligand- and complex-based computational methods was performed to analyze a new series of beta-N-biaryl ether sulfonamide hydroxamates as potent inhibitors of gelatinase A (MMP-2) and gelatinase B (MMP-9). Firstly, the similarities and differences between the binding sites of MMP-2 and MMP-9 were analyzed through sequence alignment and structural superimposition. Secondly, in order to extract structural features influencing the activities of these inhibitors, quantitative structure-activity relationship (QSAR) models using genetic algorithm-multiple linear regression (GA-MLR), comparative molecular field (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed. The proposed QSAR models could give good predictive ability for the studied inhibitors. Thirdly, docking study was employed to further explore the binding mode between the ligand and protein. The results from all the above analyses could provide the information about the similarities and differences of the binding mode between the MMP-2, MMP-9 and their potent inhibitors. The obtained results can provide very useful information for the design of new potential inhibitors.
锌依赖的基质金属蛋白酶（MMP）家族因其在许多生理和病理过程中的重要作用而被认为是一个有吸引力的靶点。在本工作中，结合基于蛋白质、配体和复合物的计算方法进行了分子建模研究，以分析一系列新型β-N-双芳基醚磺酰胺羟肟酸作为明胶酶 A（MMP-2）和明胶酶 B（MMP-9）的有效抑制剂。首先，通过序列比对和结构叠加分析 MMP-2 和 MMP-9 结合位点的相似性和差异性。其次，为了提取影响这些抑制剂活性的结构特征，采用遗传算法-多元线性回归（GA-MLR）、比较分子场（CoMFA）和比较分子相似性指数分析（CoMSIA）等定量构效关系（QSAR）模型进行了定量构效关系（QSAR）研究。所提出的 QSAR 模型可以为研究抑制剂提供良好的预测能力。第三，采用对接研究进一步探讨配体与蛋白质的结合模式。通过以上所有分析得到的结果可以提供 MMP-2、MMP-9 及其有效抑制剂之间结合模式的相似性和差异性的信息。所得结果可为设计新的潜在抑制剂提供非常有用的信息。
