Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar 160 062, Punjab, India.
J Mol Graph Model. 2009 Nov;28(4):357-67. doi: 10.1016/j.jmgm.2009.09.001. Epub 2009 Sep 6.
A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out on cycloguanil derivatives which are reported as growth inhibitors of Plasmodium falciparum clone (T9/94 RC17) which harbors A16V+S108T mutant dihydrofolate reductase (DHFR) enzyme. Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarity Indices Analysis (CoMSIA) were carried out to investigate the structural requirements for the activities of these compounds and to derive predictive models that may be used for designing novel PfDHFR enzyme inhibitors. The global minimum energy (within the search space) conformation of the most active compound (38) was obtained by using simulated annealing, and was subsequently used as a template to build the structures of the rest molecules used in the study. The CoMFA model gave statistically significant results with r(cv)(2) and r(ncv)(2) values of 0.654 and 0.951, respectively. The combination of steric, electrostatic and hydrophobic fields resulted in the best CoMSIA model with r(cv)(2) and r(ncv)(2) values of 0.669 and 0.907, respectively. The predictive abilities of the CoMFA and CoMSIA models were also evaluated using test compounds which gave r(pred)(2) values of 0.735 and 0.557, respectively. The results of bootstrapping analyses also confirmed that the generated models are robust and reliable. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The structural regions responsible for the differences in anti-plasmodial activities were analyzed with respect to their electrostatic, steric and hydrophobic nature. The results obtained from this study could be used for rational design of potent inhibitors against A16V+S108T mutant PfDHFR enzyme.
对环胍啶衍生物进行了三维定量构效关系（3D-QSAR）研究，这些衍生物被报道为携带 A16V+S108T 突变二氢叶酸还原酶（DHFR）酶的恶性疟原虫克隆（T9/94 RC17）的生长抑制剂。进行了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA），以研究这些化合物活性的结构要求，并得出可用于设计新型 PfDHFR 酶抑制剂的预测模型。通过使用模拟退火获得最活性化合物（38）的全局最低能量（在搜索空间内）构象，随后将其用作构建研究中使用的其余分子结构的模板。CoMFA 模型给出了统计学上显著的结果，交叉验证相关系数（r(cv)(2)）和非交叉验证相关系数（r(ncv)(2)）分别为 0.654 和 0.951。立体、静电和疏水场的组合导致了最佳的 CoMSIA 模型，其交叉验证相关系数（r(cv)(2)）和非交叉验证相关系数（r(ncv)(2)）分别为 0.669 和 0.907。使用测试化合物还评估了 CoMFA 和 CoMSIA 模型的预测能力，得到 r(pred)(2)值分别为 0.735 和 0.557。Bootstrapping 分析的结果也证实了生成的模型是稳健和可靠的。使用 CoMFA 和 CoMSIA 等高线图对模型进行了图形解释。根据静电、立体和疏水性，分析了对疟原虫活性差异负责的结构区域。从这项研究中获得的结果可用于合理设计针对 A16V+S108T 突变 PfDHFR 酶的有效抑制剂。
