Document 0616
 DOCN  M9650616
 TI    An approach to rapid estimation of relative binding affinities of enzyme
       inhibitors: application to peptidomimetic inhibitors of the human
       immunodeficiency virus type 1 protease.
 DT    9605
 AU    Viswanadhan VN; Reddy MR; Wlodawer A; Varney MD; Weinstein JN;
       Laboratory of Molecular Pharmacology, National Cancer Institute,;
       National Institutes of Health, Bethesda, Maryland 20892, USA.
 SO    J Med Chem. 1996 Feb 2;39(3):705-12. Unique Identifier : AIDSLINE
       MED/96160895
 AB    This report describes a method for rapid assessment of the binding
       affinities of a series of analogous ligands to an enzyme. This approach
       is based on two variables (scores), representing (i) the enthalpy of
       binding and (ii) the strength of hydrophobic interaction. The method is
       then used to evaluate the binding of 11 different peptidomimetic
       inhibitors to the HIV-1 protease. Three-dimensional structures of these
       enzyme-inhibitor complexes are modeled based on the crystal structures
       of HIV-1 protease complexes with the known inhibitors. These structures
       are minimized using the AMBER force field, and the scores of binding
       enthalpy for each of the ligands are calculated. A second score to
       represent the hydrophobic interaction between a pair of atoms uses an
       exponential function of distance between the atoms and the product of
       their atomic hydrophobicity constants. This exponential function is used
       to assess the hydrophobic interaction energy between an enzyme and its
       inhibitor and also to compute and display a 'molecular hydrophobicity
       map' as a 3D visualization tool. These methods are then applied to
       obtain trends in relative binding affinities of pairs of analogous
       inhibitors. Calculated scores agree well with corresponding results from
       thermodynamic cycle perturbation (TCP) simulations as well as
       experimental binding data. Since the proposed calculations are
       computationally cheaper and faster than TCP calculations, it is
       suggested that these scores can form the basis for rapid, preliminary
       theoretical screening of proposed derivatives of an inhibitor prior to
       TCP analysis, synthesis, and testing.
 DE    HIV Protease/*DRUG EFFECTS/METABOLISM  HIV Protease
       Inhibitors/CHEMISTRY/METABOLISM/*PHARMACOLOGY  Protein Binding
       Structure-Activity Relationship  Thermodynamics  X-Ray Diffraction
       JOURNAL ARTICLE

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