title: Molecular modeling studies, synthesis and biological evaluation of dabigatran analogues as thrombin inhibitors.
abstract: 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.
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Dong
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. Electronic address: clab@sit.edu.cn.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Ren
authors.affiliation: School of Science, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Shao
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000069604:Dabigatran / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D013917:Thrombin; D000069604:Dabigatran
keywords: 3D-QSAR; Molecular docking; Synthesis; Thrombin inhibitors; Topomer CoMFA