Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: Applying a "divide and conquer" strategy
Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a novel class of piperazine-based stromelysin-1 (MMP-3) inhibitors: Applying a "divide and conquer" strategy
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DOI：
10.1021/jm010236t
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发表时间：
2001-11-08
影响因子：
7.3
通讯作者：
Welsh, WJ
中科院分区：
文献类型：
--
作者：
Amin, EA;Welsh, WJ
利用比较分子场分析（CoMFA）技术，建立了一系列新型哌嗪基基质金属蛋白酶抑制剂（MMPIs）的三维定量构效关系（3D-QSAR）模型。利用基质溶解素-1 （MMP-3）的晶体结构来鉴定酶和抑制剂的空间和静电效应与生物活性密切相关的区域。由抑制剂子集（#10-35）组成的训练集，仅在哌嗪远端氮上的取代基（n-烷基，酰胺，尿素和磺胺）方面存在差异，产生了最具预测性的CoMFA模型，r(2)值为0.592（交叉验证）和0.989（常规）；使用两个抑制剂亚组的测试化合物进一步验证了该模型。为了获得满意的模型，需要研究各种配体构象、抑制剂亚群、排列方案和部分电荷形式。通过结合惯性对准和人工调整酶对接抑制剂，以确保抑制剂的取代基构象与MMP-3 S1-S2结合口袋的结构特征之间的互补性，取得了最大的成功。从该分析中获得的对该抑制剂组的结构-活性关系（SAR）的关键见解与实验观察到的stromelysin-1生物活性和结合位点拓扑结构的数据一致。特别是，本研究揭示了配体与部分溶剂暴露的S1-S2区域结合的空间和静电要求。
Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been obtained using comparative molecular field analysis (CoMFA) for a novel series of piperazine-based matrix metalloproteinase inhibitors (MMPIs). The crystal structure of stromelysin-1 (MMP-3) was used to identify regions of the enzyme and inhibitors where steric and electrostatic effects correlate strongly with biological activity. A training set composed of a subset of inhibitors (#10-35), which differed only with regards to the substituent (n-alkyl, amide, carbamide and sulfonamide) on the piperazine distal nitrogen, yielded the most predictive CoMFA model, with r(2) values of 0.592 (cross-validated) and 0.989 (conventional); this model was further validated using test compounds from two inhibitor subsets. Investigation of various ligand conformations, inhibitor subsets, alignment schemes and partial charge formalisms was required to obtain satisfactory models. The greatest success was achieved by incorporating inertial alignment together with manual adjustment of the enzyme-docked inhibitors to ensure complementarity between the inhibitors' substituent conformations and the structural characteristics of the MMP-3 S1-S2' binding pockets. Key insights into the structure-activity relationship (SAR) obtained from this analysis for this inhibitor set are in agreement with experimentally observed data on stromelysin-1 biological activity and binding-site topology. In particular, the present study sheds new light on the steric and electrostatic requirements for ligand binding to the partly solvent-exposed S1-S2' area.