Molecular Modeling and 3D-QSAR Studies on the Interaction Mechanism of Tripeptidyl Thrombin Inhibitors with Human α-Thrombin

The mechanism of inhibition of peptidyl inhibitors with thrombin was studied using molecular modeling, molecular mechanics, and CoMFA statistical analysis. A new procedure for the elucidation of binding conformations, BCSPL, is described and was employed to obtain the binding conformers of a series of 18 tripeptidyl thrombin inhibitors. Energetic studies and QSAR analysis of the BCSPL-derived conformers indicated a modest correlation between the calculated binding energies of the title compounds and their inhibitory activities to human α-thrombin. CoMFA analysis of the BCSPL alignment resulted in a satisfactory model of the thrombin active site.