title: Identification of HIV-1 integrase inhibitors based on a four-point pharmacophore.
abstract: The rapid emergence of human immunodeficiency virus (HIV) strains resistant to available drugs implies that effective treatment modalities will require the use of a combination of drugs targeting different sites of the HIV life cycle. Because the virus cannot replicate without integration into a host chromosome, HIV-1 integrase (IN) is an attractive therapeutic target. Thus, an effective IN inhibitor should provide additional benefit in combination chemotherapy. A four-point pharmacophore has been identified based on the structures of quinalizarin and purpurin, which were found to be potent IN inhibitors using both a preintegration complex assay and a purified enzyme assay in vitro. Searching with this four-point pharmacophore in the 'open' part of the National Cancer Institute three-dimensional structure database produced 234 compounds containing the pharmacophore. Sixty of these compounds were tested for their inhibitory activity against IN using the purified enzyme; 19 were found to be active against IN with IC50 values of less than 100 microM, among which 10 had IC50 values of less than 10 microM. These inhibitors can further serve as leads, and studies are in progress to design novel inhibitors based on the results presented in this study.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, MD 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: H E
authors.initials: HE
authors.lastname: Winslow
authors.forename: J L
authors.initials: JL
authors.lastname: Christensen
authors.forename: A
authors.initials: A
authors.lastname: Orr
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: G W
authors.initials: GW
authors.lastname: Milne
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002460:Cell Line; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D016662:Virus Integration / Q000187:drug effects
chemical_list: D000880:Anthraquinones; D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase