CoMFA modeling of human catechol O-methyltransferase enzyme kinetics.

Three-dimensional QSAR models with different charge calculation methods (MOPAC-AM1-ESP, MOPAC-AM1-Coulson and Gasteiger-Hückel) were developed for predicting all three enzyme kinetic parameters Km, Vmax and Vmax/Km for catecholic substrates of human soluble catechol O-methyltransferase (S-COMT). The empirical parameters of 45 substrates were correlated to the steric and electronic molecular fields of the substrates utilizing Comparative Molecular Field Analysis (CoMFA). Alignment rules for CoMFA were developed based on the catalytic mechanism and crystal structure of S-COMT, and the analysis was optimized using an all-space search technique. Leave-one-out and leave-n-out cross-validation (with 5 and 10 cross-validation groups) was carried out, and all developed models proved to be statistically significant with q2 values up to 0.84. The models based on MOPAC charge calculations predicted the empirical values clearly better than the Gasteiger-Hückel method. The derived CoMFA coefficient contour maps of steric and electrostatic interactions correlated clearly with the S-COMT crystallographic structures.