Document 0913
 DOCN  M9540913
 TI    A priori prediction of activity for HIV-1 protease inhibitors employing
       energy minimization in the active site.
 DT    9504
 AU    Holloway MK; Wai JM; Halgren TA; Fitzgerald PM; Vacca JP; Dorsey BD;
       Levin RB; Thompson WJ; Chen LJ; deSolms SJ; et al; Department of
       Molecular Systems, Merck Research Laboratories,; West Point,
       Pennsylvania 19486.
 SO    J Med Chem. 1995 Jan 20;38(2):305-17. Unique Identifier : AIDSLINE
       MED/95131414
 AB    We have observed a high correlation between the intermolecular
       interaction energy (Einter) calculated for HIV-1 protease inhibitor
       complexes and the observed in vitro enzyme inhibition. A training set of
       33 inhibitors containing modifications in the P1' and P2' positions was
       used to develop a regression equation which relates Einter and pIC50.
       This correlation was subsequently employed to successfully predict the
       activity of proposed HIV-1 protease inhibitors in advance of synthesis
       in a structure-based design program. This included a precursor, 47, to
       the current phase II clinical candidate, L-735,524 (51). The development
       of the correlation, its applications, and its limitations are discussed,
       and the force field (MM2X) and host molecular mechanics program
       (OPTIMOL) used in this work are described.
 DE    Binding Sites  Computer-Aided Design  Drug Design  HIV
       Protease/*CHEMISTRY/ULTRASTRUCTURE  HIV Protease Inhibitors/*CHEMISTRY
       Models, Molecular  Protein Structure, Tertiary  Structure-Activity
       Relationship  Thermodynamics  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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