       Document 0122
 DOCN  M9630122
 TI    3D-quantitative structure-activity relationships of human
       immunodeficiency virus type-1 proteinase inhibitors: comparative
       molecular field analysis of 2-heterosubstituted statine
       derivatives-implications for the design of novel inhibitors.
 DT    9603
 AU    Kroemer RT; Ettmayer P; Hecht P; SANDOZ Forschungsinstitut Ges. m.b.H,
       Vienna, Austria.
 SO    J Med Chem. 1995 Dec 8;38(25):4917-28. Unique Identifier : AIDSLINE
       MED/96105434
 AB    A set of 100 novel 2-heterosubstituted statine derivatives inhibiting
       human immunodeficiency virus type-1 proteinase has been investigated by
       comparative molecular field analysis. In order to combine the structural
       information available from X-ray analyses with a predictive quantitative
       structure-activity relationship (QSAR) model, docking experiments of a
       prototype compound into the receptor were performed, and the 'active
       conformation' was determined. The structure of the receptor was taken
       from the published X-ray analysis of the proteinase with bound MVT-101,
       the latter compound exhibiting high structural similarity with the
       inhibitors investigated. The validity of the resulting QSARs was
       confirmed in four different ways. (1) The common parameters, namely, the
       cross-validated r2 values obtained by the leave-one-out (LOO) method
       (r2cv = 0.572-0.593), and (2) the accurate prediction of a test set of
       67 compounds (q2 = 0.552-0.569) indicated a high consistency of the
       models. (3) Repeated analyses with two randomly selected
       cross-validation groups were performed and the cross-validated r2 values
       monitored. The resulting average r2 values were of similar magnitudes
       compared to those obtained by the LOO method. (4) The coefficient fields
       were compared with the steric and electrostatic properties of the
       receptor and showed a high level of compatibility. Further analysis of
       the results led to the design of a novel class of highly active
       compounds containing an additional linkage between P1' and P3'. The
       predicted activities of these inhibitors were also in good agreement
       with the experimentally determined values.
 DE    Amino Acids/*CHEMISTRY/PHARMACOLOGY  Antiviral
       Agents/*CHEMISTRY/PHARMACOLOGY  Computer Graphics  Crystallography,
       X-Ray  Drug Design  Human  Hydrogen Bonding  HIV Protease
       Inhibitors/*CHEMISTRY/PHARMACOLOGY  HIV-1/*METABOLISM  Models, Molecular
       Structure-Activity Relationship  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

