Papain catalyzed hydrolysis of aryl esters: a comparison of the Hansch, Docking and CoMFA methods

Comparative molecular field analysis (CoMFA) and binding energy calculation on enzyme-substrate (E-S) complexes, obtained by intermolecular docking, have been applied to the study of papain-catalyzed hydrolysis of phenyl N-benzoyl glycinates (HIP) and phenyl N-methanesulfonyl glycinates (MSG). Both HIP and MSG substrates only in one alignment (S, split, i.e. nonpolar substituents in one meta position and hydrophilic substituents in the other meta position) led to CoMFA models of predictive value (cross-validated r2 = 0.726 and 0.525 for HIP and MSG set, respectively), which rationalize their binding affinities. These findings confirm the mechanistic interpretation suggested on the basis of the classical 'σ-π-MR' correlation equations derived previously. CoMFA supports the prominent role of the favourable steric interactions of substituents in only one meta position and of the electrostatic forces in stabilizing the E-S complexes. However, due to its intrinsic limitations, CoMFA fails to distinguish between positive hydrophobic effects and steric tolerance in explaining the binding data variation. The binding energy values, calculated on minimized complexes obtained by docking HIP congeners in S orientation into the papain active site, were in good agreement with the experimental Km values. The results from this study bring evidence that 3-D QSAR is a helpful complement to classical QSAR models, enhancing the applicability of SAR in bioactive ligand design.