Computer-aid drug design, synthesis, and anticoagulant activity evaluation of novel dabigatran derivatives as thrombin inhibitors.

In this study, computer-aided drug design techniques were adopted to explore the structural and chemical features for dabigatran and design novel derivatives. The built 3D-QSAR models demonstrated significant statistical quality and excellent predictive ability by internal and external validation. Based on QSAR information, 11 novel dabigatran derivatives (12a-12k) were designed and predicted, then ADME prediction and molecular docking were performed. Furthermore, all designed compounds were synthesized and characterized by H NMR, C NMR and HR-MS. Finally, they were evaluated for anticoagulant activity in vitro. The activity results showed that the 10 obtained compounds exhibited comparable activity to the reference dabigatran (IC = 9.99 ± 1.48 nM), except for compound 12i. Further analysis on molecular docking was performed on three compounds (12a, 12c and 12g) with better activity (IC = 11.19 ± 1.70 nM, IC = 10.94 ± 1.85 nM and IC = 11.19 ± 1.70 nM). MD simulations (10 ns) were carried out, and their binding free energies were calculated, which showed strong hydrogen bond and pi-pi stacking interactions with key residues Gly219, Asp189 and Trp60D. The 10 novel dabigatran derivatives obtained can be further studied as anticoagulant candidate compounds.