Cl. Waller et al., 3-DIMENSIONAL QSAR OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .1. A COMFA STUDY EMPLOYING EXPERIMENTALLY-DETERMINED ALIGNMENT RULES, Journal of medicinal chemistry, 36(26), 1993, pp. 4152-4160
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.