Document 0510
 DOCN  M9480510
 TI    Three-dimensional quantitative structure-activity relationship of human
       immunodeficiency virus (I) protease inhibitors. 2. Predictive power
       using limited exploration of alternate binding modes.
 DT    9410
 AU    Oprea TI; Waller CL; Marshall GR; Center for Molecular Design,
       Washington University School of; Medicine, St. Louis, Missouri
       63130-4866.
 SO    J Med Chem. 1994 Jul 8;37(14):2206-15. Unique Identifier : AIDSLINE
       MED/94309074
 AB    NewPred, a semiautomated procedure to evaluate alternate binding modes
       and assist three dimensional quantitative structure-activity
       relationship (3D-QSAR) studies in predictive power evaluation is
       exemplified with a series of 30 human immunodeficiency virus 1 protease
       (HIV PR) inhibitors. Five comparative molecular field analysis (CoMFA)
       models (Waller, 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 investigate the binding mode in P1' and P2'. Twelve
       dihyroxyethylenes (set B) (Thaisrivongs, 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 of the test set, but not investigated with
       NewPred. Each compound was aligned in accordance to predefined alignment
       rules for the training set prior to the inclusion in the test set
       (except for set C). Using NewPred, geometrically different conformers
       for each compound were generated and individually relaxed in the HIV-PR
       binding site. Energy comparisons allowed selection of lowest energy
       structures to be included in the test set. Only in vacuo minimized
       conformers derived from low-energy complexes were used to determine the
       predictive power of the five models (predictive r2 varied from 0.1 to
       0.7 when two chemical and statistical outliers were excluded). Our
       models correctly predict the poor inhibitor activity of
       1(S)-amino-2(R)-hydroxyindan-containing peptides (set B), which is
       explained and interpreted from a 3D-QSAR perspective. The use of a new,
       flexibility-based, semiautomated method to explore alternate binding
       models for 3D-QSAR models is demonstrated.
 DE    Amino Acid Sequence  Binding Sites  HIV Protease  HIV Protease
       Inhibitors/*CHEMISTRY/PHARMACOLOGY  Models, Molecular  Molecular
       Conformation  Molecular Sequence Data  Structure-Activity Relationship
       Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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