3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .2. PREDICTIVE POWER USING LIMITED EXPLORATION OF ALTERNATE BINDING MODES

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.