3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF ANGIOTESIN-CONVERTING ENZYME AND THERMOLYSIN INHIBITORS .2. A COMPARISON OF COMFA MODELS INCORPORATING MOLECULAR-ORBITAL FIELDS AND DESOLVATION FREE-ENERGIES BASED ON ACTIVE-ANALOG AND COMPLEMENTARY-RECEPTOR-FIELD ALIGNMENT RULES

The utility of comparative molecular field analysis (CoMFA), a three-d imensional Quantitative Structure-Activity Relationship (3-D QSAR) par adigm, as a tool to aid in the development of predictive models has be en previously addressed (Depriest, S.D. et al., J. Am. Chem. Soc. 1993 , in press). Although predictive correlations were obtained for angiot ensin-converting and thermolysin inhibitors, certain inadequacies of t he CoMFA technique were noted. Primarily, CoMFA steric and electrostat ic fields alone do not fully characterize the zinc-ligand interaction. Previously, this was partially rectified by the inclusion of indicato r variables into the QSAR table to designate the class of zinc-binding ligand. Recent advances in molecular modeling technology have allowed us to further address this limitation of the preceding study. Using m olecular orbital fields derived from semiempirical calculations as add itional descriptors in the QSAR table, predictive correlations were pr oduced based on CoMFA and molecular orbital fields alone-indicator var iables no longer being necessary. Arbitrary information concerning the alignment of molecules under study within the active-site introduces ambiguities into the CoMFA study. Crystallographic information detaili ng the binding mode of several thermolysin enzyme inhibitors has previ ously been used as a guide for the alignment of additional, noncrystal lized, inhibitors. However, this process was complicated by the lack o f parameters for zinc in the molecular mechanical force field. Therefo re, zinc-ligand interactions were ignored during the standard minimiza tion procedure. The use of field-fit minimization using complementary receptor fields as templates is presented as a possible solution to th e problem. Predictive correlations were obtained from analyses based o n this method of molecular alignment. The availability of crystallogra phic data for thermolysin enzyme-inhibitor complexes allowed for an al ternate definition of the CoMFA region. Herein, promising results from analyses using actual receptor active-site atom probe atoms are prese nted.