文献类型：期刊文献

英文题名：Molecular modeling studies, synthesis and biological evaluation of dabigatran analogues as thrombin inhibitors

作者：Dong, Ming-Hui[1];Chen, Hai-Feng[1];Ren, Yu-Jie[1];Shao, Fang-Ming[2]

机构：[1]Shanghai Inst Technol, Coll Chem & Environm Engn, Shanghai 201418, Peoples R China;[2]E China Univ Sci & Technol, Sch Sci, Shanghai 200237, Peoples R China

年份：2016

卷号：24

期号：2

起止页码：73

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000367234300002)】；

基金：This work was supported by the "industry-university-research institutions" collaborative innovation fund (10120K158014) of Shanghai Institute of Technology.

语种：英文

外文关键词：Thrombin inhibitors; 3D-QSAR; Topomer CoMFA; Molecular docking; Synthesis

摘要：In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q(2) and a non-cross-validation r(2), which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.