Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, People's Republic of China.
J Mol Model. 2012 Mar;18(3):973-90. doi: 10.1007/s00894-011-1134-0. Epub 2011 Jun 5.
Presently, an in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase (FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The CoMFA and CoMSIA models using 51 molecules in the training set gave r (cv) (2) values of 0.675 and 0.619, r ( 2 ) values of 0.985 and 0.979, respectively. The systemic external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r (0) (2) values of 0.995 and 0.994, r (m(test)) (2) values of 0.887 and 0.860, respectively. The 3D contour maps of the CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship for the inhibitors. Molecular docking studies revealed that a phosphonic group was essential for binding to the AMP binding site, and some key features were also identified. The analyses of the 3D contour plots and molecular docking results permitted interesting conclusions about the effects of different substituent groups at different positions of the common scaffold, which might guide the design of novel FBPase inhibitors with higher activity and bioavailability. A set of 60 new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.
目前，我们使用 CoMFA/CoMSIA 和分子对接方法，对一系列 63 种含膦酸的噻唑衍生物作为果糖-1,6-二磷酸酶 (FBPase) 抑制剂进行了计算机模拟。使用训练集中的 51 个分子构建的 CoMFA 和 CoMSIA 模型，其交叉验证相关系数 (r(cv)(2)) 值分别为 0.675 和 0.619，拟合相关系数 (r(2)) 值分别为 0.985 和 0.979。系统外部验证表明，我们的 CoMFA 和 CoMSIA 模型具有较高的预测能力，其验证相关系数 (r(0)(2)) 值分别为 0.995 和 0.994，验证均方根误差 (r(m(test))(2)) 值分别为 0.887 和 0.860。CoMFA 和 CoMSIA 的三维等高线图为抑制剂的结构-活性关系提供了平滑且易于解释的解释。分子对接研究表明，膦酸基团对于与 AMP 结合位点结合是必需的，并且还确定了一些关键特征。3D 等高线图和分子对接结果的分析允许对不同取代基在共同支架不同位置的不同影响进行有趣的结论，这可能指导设计具有更高活性和生物利用度的新型 FBPase 抑制剂。利用本研究中揭示的结果设计了一组 60 种新的类似物，并在开发的模型中预测了它们具有显著提高的效力。这些发现对于辅助设计具有改善的生物学响应的新型果糖-1,6-二磷酸酶抑制剂非常有用。
