title: Mining the NCI antiviral compounds for HIV-1 integrase inhibitors.
abstract: HIV-1 integrase (IN) is an essential enzyme for effective viral replication and is a validated target for the development of antiretroviral drugs. Currently, there are no approved drugs targeting this enzyme. In this study, we have identified 11 structurally diverse small-molecule inhibitors of IN. These compounds have been selected by mining the moderately active antiviral molecules from a collection of 90,000 compounds screened by the National Cancer Institute (NCI) Antiviral Program. These compounds, which were screened at the NCI during the past 20 years, resulted in approximately 4000 compounds labeled as 'moderately active.' In our study, chalcone 11 shows the most potent activity with an IC(50) of 2+/-1 microM against purified IN in the presence of both Mn(2+) and Mg(2+) as cofactors. Docking simulations using the 11 identified inhibitors as a training set have elucidated two unique binding areas within the active site: the first encompasses the conserved D64-D116-E152 motif, while the other involves the flexible loop region formed by amino acid residues 140-149. The tested inhibitors exhibit favorable interactions with important amino acid residues through van der Waals and H-bonding contacts.
authors.affiliation: Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Deng
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Barchi
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009316:National Institutes of Health (U.S.); D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase