Molecular docking and topomer CoMFA research of phenyl acetamides derivatives as direct thrombin inhibitors

The molecular docking was employed to study the binding of 37 phenyl acetamides derivatives to human α-thrombin. The results showed that hydrogen bonding interactions between Asp189 and basic group of P1 moiety of inhibitors, hydrophobic interactions between Tyr60A, Trp60D and benzene ring of P2 moiety, electrostatic interactions between His215 and negative-charged substituent of the benzene ring, hydrophobic interactions and steric hindrance between the binding site S3 and P3 moiety were the dominant factors affecting the binding affinities. Topomer comparative molecular field analysis (Topomer CoMFA) was then used to establish models for virtual screening, which resulted in a reliable computational model. The number of principal components, r², q² (leave-one-out, LOO), r²_pred of the optimal Topomer CoMFA model were 3, 0.869, 0.544 and 0.873, respectively. The results showed that the external predictive abilities of Topomer CoMFA model was much better than that of the traditional CoMFA and CoMSIA models. The structure-activity relationships obtained from Topomer CoMFA model were in agreement with the docking results.