title: Discovery of structurally diverse HIV-1 integrase inhibitors based on a chalcone pharmacophore.
abstract: Recently, we reported small-molecule chalcones as a novel class of HIV-1 integrase (IN) inhibitors. The most potent compound showed an IC50 value of 2 microM for both IN-mediated 3'-processing and strand transfer reactions. To further utilize the chalcones, we developed pharmacophore models to identify chemical signatures important for biological activity. The derived models were validated with a collection of published inhibitors, and then were applied to screen a subset of our small molecule database. We tested 71 compounds in an in vitro assay specific for IN enzymatic activity. Forty-four compounds showed inhibitory potency<100 microM, and four of them exhibited IC50 values<10 microM. One compound, 62, with an IC50 value of 0.6 microM, displayed better potency than the original chalcone 2 against the strand transfer process. This study demonstrates the systematic use of pharmacophore technologies to discover novel structurally diverse inhibitors based on lead molecules that would exhibit poor characteristics in vivo. The identified compounds have the potential to exhibit favorable pharmacokinetic and pharmacodynamic profiles.
authors.affiliation: Department of Pharmacology and 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: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Laith Q
authors.initials: LQ
authors.lastname: Al-Mawsawi
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Rosendo A
authors.initials: RA
authors.lastname: Yunes
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bolger
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D002384:Catalysis; D002599:Chalcone / Q000737:chemistry* / Q000494:pharmacology*; D030562:Databases, Protein; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D002599:Chalcone; D019427:HIV Integrase