MOLECULAR MODELING AND 3D-QSAR STUDIES ON THE INTERACTION MECHANISM OF TRIPEPTIDYL THROMBIN INHIBITORS WITH HUMAN ALPHA-THROMBIN

The mechanism of inhibition of peptidyl inhibitors with thrombin was s tudied using molecular modeling, molecular mechanics, and CoMFA statis tical analysis. A new procedure for the elucidation of binding conform ations, BCSPL, is described and was employed to obtain the binding con formers of a series of 18 tripeptidyl thrombin inhibitors. Energetic s tudies and QSAR analysis of the BCSPL-derived conformers indicated a m odest correlation between the calculated binding energies of the title compounds and their inhibitory activities to human a-thrombin. CoMFA analysis of the BCSPL alignment resulted in a satisfactory model of th e thrombin active site.