结合分子对接的三维定量构效关系建模法鉴定鸟嘌呤衍生物作为甲基化鸟嘌呤-DNA甲基转移酶抑制剂的结构特征

Identification of the Structural Features of Guanine Derivatives as MGMT Inhibitors Using 3D-QSAR Modeling Combined with Molecular Docking.

作者信息

Sun Guohui, Fan Tengjiao, Zhang Na, Ren Ting, Zhao Lijiao, Zhong Rugang

机构信息

Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.

出版信息

Molecules. 2016 Jun 23;21(7):823. doi: 10.3390/molecules21070823.

DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT), which plays an important role in inducing drug resistance against alkylating agents that modify the O⁶ position of guanine in DNA, is an attractive target for anti-tumor chemotherapy. A series of MGMT inhibitors have been synthesized over the past decades to improve the chemotherapeutic effects of O⁶-alkylating agents. In the present study, we performed a three-dimensional quantitative structure activity relationship (3D-QSAR) study on 97 guanine derivatives as MGMT inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Three different alignment methods (ligand-based, DFT optimization-based and docking-based alignment) were employed to develop reliable 3D-QSAR models. Statistical parameters derived from the models using the above three alignment methods showed that the ligand-based CoMFA (Qcv² = 0.672 and Rncv² = 0.997) and CoMSIA (Qcv² = 0.703 and Rncv² = 0.946) models were better than the other two alignment methods-based CoMFA and CoMSIA models. The two ligand-based models were further confirmed by an external test-set validation and a Y-randomization examination. The ligand-based CoMFA model (Qext² = 0.691, Rpred² = 0.738 and slope k = 0.91) was observed with acceptable external test-set validation values rather than the CoMSIA model (Qext² = 0.307, Rpred² = 0.4 and slope k = 0.719). Docking studies were carried out to predict the binding modes of the inhibitors with MGMT. The results indicated that the obtained binding interactions were consistent with the 3D contour maps. Overall, the combined results of the 3D-QSAR and the docking obtained in this study provide an insight into the understanding of the interactions between guanine derivatives and MGMT protein, which will assist in designing novel MGMT inhibitors with desired activity.

DNA修复酶O⁶-甲基鸟嘌呤-DNA甲基转移酶（MGMT）在诱导对使DNA中鸟嘌呤O⁶位置发生修饰的烷化剂产生耐药性方面发挥着重要作用，是抗肿瘤化疗的一个有吸引力的靶点。在过去几十年中已合成了一系列MGMT抑制剂，以提高O⁶-烷化剂的化疗效果。在本研究中，我们使用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法，对97种作为MGMT抑制剂的鸟嘌呤衍生物进行了三维定量构效关系（3D-QSAR）研究。采用三种不同的比对方法（基于配体的比对、基于密度泛函理论（DFT）优化的比对和基于对接的比对）来建立可靠的3D-QSAR模型。使用上述三种比对方法从模型得出的统计参数表明，基于配体的CoMFA（交叉验证系数Qcv² = 0.672，非交叉验证系数Rncv² = 0.997）和CoMSIA（交叉验证系数Qcv² = 0.703，非交叉验证系数Rncv² = 0.946）模型优于基于其他两种比对方法的CoMFA和CoMSIA模型。通过外部测试集验证和Y随机化检验进一步证实了这两个基于配体的模型。观察到基于配体的CoMFA模型（外部验证系数Qext² = 0.691，预测系数Rpred² = 0.738，斜率k = 0.91）具有可接受的外部测试集验证值，而CoMSIA模型（外部验证系数Qext² = 0.307，预测系数Rpred² = 0.4，斜率k = 0.719）则不然。进行了对接研究以预测抑制剂与MGMT的结合模式。结果表明，所获得的结合相互作用与3D等高线图一致。总体而言，本研究中获得的3D-QSAR和对接的综合结果为深入了解鸟嘌呤衍生物与MGMT蛋白之间的相互作用提供了思路，这将有助于设计具有所需活性的新型MGMT抑制剂。