A 3D-QSAR analysis of prolyl endopeptidase inhibitors

A set of 44 previously synthesized and tested prolyl endopeptidase (PEP) in hibitors were investigated using comparative molecular field analysis (CoMF A). CoMFA models were developed for two conceivable alignments of the molec ules: one based on a template structure in its global conformational energy minimum (bent form), and the other based on a template structure in a simi lar conformation to related molecules from the co-crystallized enzyme-inhib itor complex (linear form). Good CoMFA models were obtained for both alignm ents with q(2) values of 0.709 for the bent form and 0.652 for the linear f orm. The CoMFA models were validated by dividing the set of molecules into a training set and a validation set: the r(2) value between the measured an d predicted inhibitory activities of the molecules in the validation set wa s 0.773 for the bent form and 0.645 for the linear form. The derived CoMFA models reveal several interaction sites between the inhibitor molecules and the PEP enzyme, but do not differentiate between the bent and linear forms .