PAPAIN-CATALYZED HYDROLYSIS OF ARYL ESTERS - A COMPARISON OF THE HANSCH, DOCKING AND COMFA METHODS

Comparative molecular field analysis (CoMFA) and binding energy calcul ation 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 gly cinates (MSG). Both HIP and MSG substrates only in one alignment (S, s plit, i.e. nonpolar substituents in one meta position and hydrophilic substituents in the other meta position) led to CoMFA models of predic tive value (cross-validated r(2) = 0.726 and 0.525 for HIP and MSG set , respectively), which rationalize their binding affinities. These fin dings confirm the mechanistic interpretation suggested on the basis of the classical ''sigma-pi-MR'' correlation equations derived previousl y. CoMFA supports the prominent role of the favourable steric interact ions of substituents in only one meta position and of the electrostati c forces in stabilizing the E-S complexes. However, due to its intrins ic limitations, CoMFA fails to distinguish between positive hydrophobi c effects and steric tolerance in explaining the binding data variatio n. The binding energy values, calculated on minimized complexes obtain ed by docking HIP congeners in S orientation into the papain active si te, were in good agreement with the experimental Km values. The result s from this study bring evidence that 3-D QSAR is a helpful complement to classical QSAR models, enhancing the applicability of SAR in bioac tive ligand design.