       Document 0460
 DOCN  M9640460
 TI    A preference-based free-energy parameterization of enzyme-inhibitor
       binding. Applications to HIV-1-protease inhibitor design.
 DT    9604
 AU    Wallqvist A; Jernigan RL; Covell DG; Frederick Cancer Research and
       Development Center, National Cancer; Institute, Frederick, Maryland
       21702, USA.
 SO    Protein Sci. 1995 Sep;4(9):1881-903. Unique Identifier : AIDSLINE
       MED/96100655
 AB    The interface between protein receptor-ligand complexes has been studied
       with respect to their binary interatomic interactions. Crystal structure
       data have been used to catalogue surfaces buried by atoms from each
       member of a bound complex and determine a statistical preference for
       pairs of amino-acid atoms. A simple free energy model of the
       receptor-ligand system is constructed from these atom-atom preferences
       and used to assess the energetic importance of interfacial interactions.
       The free energy approximation of binding strength in this model has a
       reliability of about +/- 1.5 kcal/mol, despite limited knowledge of the
       unbound states. The main utility of such a scheme lies in the
       identification of important stabilizing atomic interactions across the
       receptor-ligand interface. Thus, apart from an overall hydrophobic
       attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci
       3:717-729), a rich variety of specific interactions is observed. An
       analysis of 10 HIV-1 protease inhibitor complexes is presented that
       reveals a common binding motif comprised of energetically important
       contacts with a rather limited set of atoms. Design improvements to
       existing HIV-1 protease inhibitors are explored based on a detailed
       analysis of this binding motif.
 DE    Alcohols/CHEMISTRY  Binding Sites  Chemistry, Physical  *Drug Design
       Electrochemistry  Hydrogen Bonding  HIV Protease/CHEMISTRY/*METABOLISM
       HIV Protease Inhibitors/*CHEMISTRY/*METABOLISM  HIV-1/*ENZYMOLOGY
       Models, Chemical  Models, Molecular  Protein Binding  Sulfhydryl
       Compounds/CHEMISTRY  Support, U.S. Gov't, P.H.S.  Thermodynamics
       JOURNAL ARTICLE

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

