Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes

A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-ba sed method were applied on a database holding the 3D structures of 29 throm bin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimenta lly determined binding (Ki) data. CoMFA, which only uses the information of the inhibitors, performed best (r = 0.99, q(2) = 0.46, N = 29) when HF 6-3 1G charges were used in combination with a pharmacophore-based alignment. I nclusion of hydrophobic fields did not lead to improvements. The interactio n energy-based approach uses the information of the whole thrombin-inhibito r complex. A statistically significant correlation (r = 0.74, N = 14) could only be obtained for a subset of the database containing the high resoluti on structures. Geometry optimization of the ligand only in combination with downscaled electrostatics performed best.