3-DIMENSIONAL QSAR OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .1. A COMFA STUDY EMPLOYING EXPERIMENTALLY-DETERMINED ALIGNMENT RULES

Comparative molecular field analysis (CoMFA), a three-dimensional, qua ntitative structure-activity relationship (QSAR) paradigm, was used to examine the correlations between the calculated physicochemical prope rties and the in vitro activities of a series of human immunodeficienc y virus (HIV-1) protease inhibitors. The training set consisted of 59 molecules from five structurally-diverse transition-state isostere cla sses: hydroxyethylamine, statine, norstatine, keto amide, and dihydrox yethylene. The availability of X-ray crystallographic data for at leas t one representative from each class bound to the protease provided in formation regarding not only the active conformation of each ligand bu t also, via superimposition of protease backbones, the relative positi ons of each ligand with respect to one another in the active site of t he enzyme. Once aligned, these molecules served as templates on which additional congeners were field-fit minimized. Additional alignment ru les were derived from minimizations of the ligands in the active site of the semirigid protease. The predictive ability of each resultant mo del was evaluated using a test set comprised of molecules containing a novel transition-state isostere: hydroxyethylurea. Crystallographic s tudies (Getman, D. P.; et al. J. Med. Chem. 1993, 36, 288-291) indicat ed an unexpected binding mode for this series of compounds which precl uded the use of the field-fit minimization alignment technique. The te st set molecules were, therefore, subjected to a limited systematic se arch in conjunction with active-site minimization. The conformer of ea ch molecule expressing the lowest interaction energy with the active s ite was included in the test set. Field-fit minimization of neutral mo lecules to crystal ligands and active-site minimizations of protonated ligands yielded predictive correlations for HIV-1 protease inhibitors . The use of crystallographic data in the determination of alignment r ules and field-fit minimization as a molecular alignment tool in the a bsence of direct experimental data regarding binding modes is strongly supported by these results.