Document 0686
 DOCN  M9590686
 TI    Finding new inhibitors of the hiv-1 integrase: structure
 DT    9509
 AU    Weinstein JN; Raghavan K; Buolamwini J; Zaharevitz D; Paull KD; Mazumder
       A; Fesen M; Kohn KW; Pommier Y; Lab of Molecular Pharmacology and
       Information Technology Branch,; Developmental Therapeutics Program, DCT,
       NCI, Bethesda, Md.
 SO    NIH Conf Retroviral Integrase. 1995 Jan 19-20;:(Participants' abstracts
       and posters, abstract no. 11). Unique Identifier : AIDSLINE
       AIDS/95920033
 AB    The aim of this study was to identify new compounds active against the
       HIV-1 integrase using as a guide the hypothesis (Fesen, et al., Biochem.
       Pharmacol., in press) that ortho-OH groups favor inhibition (of both the
       cleavage and integration steps). Fesen, et al. (PNAS 90:2399, 1993) have
       identified inhibitors of this enzyme as potential therapeutic agents for
       AIDS. An assay using recombinant HIV-1 integrase and oligonucleotides
       identified 15 flavone analogues active against the enzyme at <100 micro
       M. We analyzed those molecules (and in some cases a total of 44) by 3
       different quantitative structure-activity relationship (QSAR) methods:
       comparative molecular field analysis (CoMFA), electrotopological state
       (E-state) analysis, and back-propagation neural networks. To identify
       new inhibitors, we also developed a set of pharmacophoric descriptors in
       Chem-X and searched the NCI database of 400,000 3-D structures.
       Compounds predicted to be active are being tested in the integrase assay
       and in the NCI AIDS drug screen in CEM-SS cells. CoMFA, E-state, and
       neural network analyses all support the ortho-OH hypothesis. OH
       substituents at positions C5, C6, C31, and/or C5' appear favorable. When
       a flavanone molecule without ortho hydroxyls was found to inhibit the
       integrase, it was built and analyzed in the Sybyl molecular modeling
       package. In one of its lowest-energy states, the molecule folds on
       itself so that its two phenolic rings pi-pi stack with 2.78-  separation
       between OH centers -- in good agreement with the 2.79- separation
       between ortho OH groups. Searches of the NCI database for molecules
       similar to the flavone, to the flavanone, and to the other inhibitors of
       the integrase yielded compounds that are currently being tested for
       activity. In conclusion, molecular structure analysis, 3-D structural
       database searching, and experimental assays can be combined to identify
       new potential inhibitors of the HIV- 1 integrase. Work of J.N.W. and
       Y.P. supported in part by the NIH Intramural AIDS Targeted Antiviral
       Program.
 DE    Acquired Immunodeficiency Syndrome/DRUG THERAPY  Antiviral
       Agents/CHEMISTRY/PHARMACOLOGY/THERAPEUTIC USE  DNA
       Nucleotidyltransferases/*ANTAGONISTS & INHIB  Databases, Factual  Drug
       Design  Drug Screening/METHODS  Enzyme
       Inhibitors/*CHEMISTRY/PHARMACOLOGY  Flavones/*CHEMISTRY/PHARMACOLOGY
       HIV-1/*ENZYMOLOGY  Models, Molecular  Recombinant Proteins
       Structure-Activity Relationship  MEETING ABSTRACT

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