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

A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-based method were applied on a database holding the 3D structures of 29 thrombin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimentally determined binding (Ki) data. CoMFA, which only uses the information of the inhibitors, performed best (r = 0.99, q2 = 0.46, N = 29) when HF 6-31G charges were used in combination with a pharmacophore-based alignment. Inclusion of hydrophobic fields did not lead to improvements. The interaction energy-based approach uses the information of the whole thrombin-inhibitor complex. A statistically significant correlation (r = 0.74, N = 14) could only be obtained for a subset of the database containing the high resolution structures. Geometry optimization of the ligand only in combination with downscaled electrostatics performed best.