       Document 0303
 DOCN  M9640303
 TI    Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside
       inhibitors: total energy of complexation as a predictor of drug
       placement and activity.
 DT    9604
 AU    Kroeger Smith MB; Rouzer CA; Taneyhill LA; Smith NA; Hughes SH; Boyer
       PL; Janssen PA; Moereels H; Koymans L; Arnold E; et al; ABL-Basic
       Research Program, NCI-Frederick Cancer Research and; Development Center,
       Maryland 21702, USA.
 SO    Protein Sci. 1995 Oct;4(10):2203-22. Unique Identifier : AIDSLINE
       MED/96117671
 AB    Computer modeling studies have been carried out on three nonnucleoside
       inhibitors complexed with human immunodeficiency virus type 1 (HIV-1)
       reverse transcriptase (RT), using crystal coordinate data from a subset
       of the protein surrounding the binding pocket region. Results from the
       minimizations of solvated complexes of
       2-cyclopropyl-4-methyl-5,11-dihydro-5H-dipyrido[3,2-b :2',3'-e][1,4]
       diazepin-6-one (nevirapine), alpha-anilino-2, 6-dibromophenylacetamide
       (alpha-APA), and
       8-chloro-tetrahydro-imidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-th- i one
       (TIBO) show that all three inhibitors maintain a very similar
       conformational shape, roughly overlay each other in the binding pocket,
       and appear to function as pi-electron donors to aromatic side-chain
       residues surrounding the pocket. However, side-chain residues adapt to
       each bound inhibitor in a highly specific manner, closing down around
       the surface of the drug to make tight van der Waals contacts.
       Consequently, the results from the calculated minimizations reveal that
       only when the inhibitors are modeled in a site constructed from
       coordinate data obtained from their particular RT complex can the
       calculated binding energies be relied upon to predict the correct
       orientation of the drug in the pocket. In the correct site, these
       binding energies correlate with EC50 values determined for all three
       inhibitors in our laboratory. Analysis of the components of the binding
       energy reveals that, for all three inhibitors, solvation of the drug is
       endothermic, but solvation of the protein is exothermic, and the sum
       favors complex formation. In general, the protein is energetically more
       stable and the drug less stable in their complexes as compared to the
       reactant conformations. For all three inhibitors, interaction with the
       protein in the complex is highly favorable. Interactions of the
       inhibitors with individual residues correlate with crystallographic and
       site-specific mutational data. pi-Stacking interactions are important in
       binding and correlate with drug HOMO RHF/6-31G* energies. Modeling
       results are discussed with respect to the mechanism of complex formation
       and the design of nonnucleoside inhibitors that will be more effective
       against mutants of HIV-1 RT that are resistant to the currently
       available drugs.
 DE    Acetamides/CHEMISTRY/METABOLISM  Benzodiazepines/CHEMISTRY/METABOLISM
       Binding Sites  Comparative Study  Computer Simulation  Human
       HIV-1/*ENZYMOLOGY  Imidazoles/CHEMISTRY/METABOLISM  Kinetics
       Mathematics  *Models, Molecular  Molecular Conformation  *Protein
       Conformation  *Protein Structure, Secondary
       Pyridines/CHEMISTRY/METABOLISM  Reverse Transcriptase
       Inhibitors/*CHEMISTRY/METABOLISM  RNA-Directed DNA
       Polymerase/*CHEMISTRY/*METABOLISM  Structure-Activity Relationship
       Support, Non-U.S. Gov't  Support, U.S. Gov't, Non-P.H.S.  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).

