3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .2. PREDICTIVE POWER USING LIMITED EXPLORATION OF ALTERNATE BINDING MODES
Ti. Oprea et al., 3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .2. PREDICTIVE POWER USING LIMITED EXPLORATION OF ALTERNATE BINDING MODES, Journal of medicinal chemistry, 37(14), 1994, pp. 2206-2215
NewPred, a semiautomated procedure to evaluate alternate binding modes
and assist three dimensional quantitative structure-activity relation
ship (SD-QSAR) studies in predictive power evaluation is exemplified w
ith a series of 30 human immunodeficiency virus 1 protease (HIV PR) in
hibitors. Five comparative molecular field analysis (CoMFA) models (Wa
ller, C. L.; et al. J. Med. Chem. 1993, 36, 4152-4160) based on 59 HIV
-PR inhibitors were tested. The test set included 18 compounds (set A)
having a different transition state isostere (TSI), hydroxyethylurea
(Getman, D. P.; et al. J. Med. Chem. 1993, 36, 288-291), to investigat
e the binding mode in P1' and P2'. Twelve dihyroxyethylenes (set B) (T
haisrivongs, S.; et al. J. Med. Chem. 1993, 36, 941-952) were used to
investigate binding in P2 and P3 as well as in P2' and P3'. Six other
compounds with known or inferred binding structure (set C) were part o
f the test set, but not investigated with NewPred. Each compound was a
ligned in accordance to predefined alignment rules for the training se
t prior to the inclusion in the test set (except for set C). Using New
Pred, geometrically different conformers for each compound were genera
ted and individually relaxed in the HIV-PR binding site. Energy compar
isons allowed selection of lowest energy structures to be included in
the test set. Only in vacuo minimized conformers derived from low-ener
gy complexes were used to determine the predictive power of the five m
odels (predictive r(2) varied from 0.1 to 0.7 when two chemical and st
atistical outliers were excluded). Our models correctly predict the po
or inhibitor activity of 1 (S)-amino-2(R)-hydroxyindan-containing pept
ides (set B), which is explained and interpreted from a 3D-QSAR perspe
ctive. The use of a new, flexibility-based, semiautomated method to ex
plore alternate binding modes for 3D-QSAR models is demonstrated.