Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P(1) (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P(2) (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P(3) (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S(1), S(2), and S(3) subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure–activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes.