ABSTRACT

Gelatinases [gelatinase A – matrix metalloproteinase-2 (MMP-2), gelatinase B – matrix metalloproteinase-9 (MMP-9)] play key roles in many disease conditions including cancer. Despite some research work on gelatinases inhibitors both jointly and individually had been reported, challenges still exist in achieving potency as well as selectivity. Here in part I of a series of work, we have reported the structural requirement of some arylsulfonamides. In particular, regression-based 2D-QSARs, topomer CoMFA (comparative molecular field analysis) and Bayesian classification models were constructed to refine structural features for attaining better gelatinase inhibitory activity. The 2D-QSAR models exhibited good statistical significance. The descriptors nsssN, SHBint6, SHBint7, PubchemFP629 were directly correlated with the MMP-2 binding affinities whereas nsssN, SHBint10 and AATS2i were directly proportional to MMP-9 binding affinities. The topomer CoMFA results indicated that the steric and electrostatic fields play key roles in gelatinase inhibition. The established Naïve Bayes prediction models were evaluated by fivefold cross validation and an external test set. Furthermore, important molecular descriptors related to MMP-2 and MMP-9 binding affinities and some active/inactive fragments were identified. Thus, these observations may be helpful for further work of aryl sulphonamide based gelatinase inhibitors in future.

摘要

明胶酶 [明胶酶 A – 基质金属蛋白酶-2 (MMP-2)，明胶酶 B – 基质金属蛋白酶-9 (MMP-9)] 在包括癌症在内的许多疾病中发挥着关键作用。尽管已经报道了一些关于明胶酶抑制剂的联合和单独研究工作，但在实现效力和选择性方面仍然存在挑战。在一系列工作的第一部分，我们报告了一些芳基磺酰胺的结构要求。特别是，构建了基于回归的 2D-QSAR、拓扑异构体 CoMFA（比较分子场分析）和贝叶斯分类模型来改进结构特征，以获得更好的明胶酶抑制活性。2D-QSAR 模型表现出良好的统计显着性。描述符 nsssN、SHBint6、SHBint7、PubchemFP629 与 MMP-2 结合亲和力直接相关，而 nsssN、SHBint10 和 AATS2i 与 MMP-9 结合亲和力成正比。拓扑异构体 CoMFA 结果表明空间和静电场在明胶酶抑制中起关键作用。已建立的朴素贝叶斯预测模型通过五重交叉验证和外部测试集进行评估。此外，还鉴定了与 MMP-2 和 MMP-9 结合亲和力和一些活性/非活性片段相关的重要分子描述符。因此，这些观察结果可能有助于未来基于芳基磺酰胺的明胶酶抑制剂的进一步工作。已建立的朴素贝叶斯预测模型通过五重交叉验证和外部测试集进行评估。此外，还鉴定了与 MMP-2 和 MMP-9 结合亲和力和一些活性/非活性片段相关的重要分子描述符。因此，这些观察结果可能有助于未来基于芳基磺酰胺的明胶酶抑制剂的进一步工作。已建立的朴素贝叶斯预测模型通过五重交叉验证和外部测试集进行评估。此外，还鉴定了与 MMP-2 和 MMP-9 结合亲和力和一些活性/非活性片段相关的重要分子描述符。因此，这些观察结果可能有助于未来基于芳基磺酰胺的明胶酶抑制剂的进一步工作。