A combined molecular modeling study on gelatinases and their potent inhibitors
A combined molecular modeling study on gelatinases and their potent inhibitors
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DOI：
10.1002/jcc.21279
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发表时间：
2010-01
影响因子：
3
通讯作者：
Lili Xi;Juan Du;Shuyan Li;Jiazhong Li;Huanxiang Liu;X. Yao
中科院分区：
文献类型：
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作者：
Lili Xi;Juan Du;Shuyan Li;Jiazhong Li;Huanxiang Liu;X. Yao
锌依赖性基质金属蛋白酶（MMP）家族因其在许多生理和病理过程中发挥重要作用而被认为是一个有吸引力的靶点。在本研究中，结合基于蛋白质、配体和复合物的计算方法，进行了一项分子建模研究，以分析一系列新的β - N -联芳基醚磺酰胺羟酸盐作为明胶酶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了MMP‐2和MMP‐9结合位点的异同。其次，为了提取影响这些抑制剂活性的结构特征，建立了基于遗传算法-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）的定量构效关系（QSAR）模型。所建立的QSAR模型对所研究的抑制剂具有较好的预测能力。再次，采用对接研究，进一步探索配体与蛋白质的结合方式。上述分析的结果可以提供MMP‐2、MMP‐9及其有效抑制剂之间结合模式的异同信息。所得结果可为新型潜在抑制剂的设计提供非常有用的信息。©2009 Wiley期刊公司计算机学报，2010
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 β‐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. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010