title: Quinolone 3-carboxylic acid pharmacophore: design of second generation HIV-1 integrase inhibitors.
abstract: Two decades of intensive research efforts have led to the discovery of a large number of HIV-1 integrase (IN) inhibitors. Recently, the United States Food and Drug Administration (US FDA) approved MK-0518, or raltegravir ( 1), as the first IN inhibitor for HIV/AIDS treatment. Growing clinical evidence also demonstrates that the emergence of HIV-1 virus strains bearing IN amino acid substitutions that confer resistance to IN inhibitors is inevitable. The discovery of second generation inhibitors with potency against viral strains bearing drug resistant IN substitutions is necessary for ongoing effective treatment of viral infections. We generated common feature pharmacophore hypotheses using a training set of quinolone 3-carboxylic acid IN inhibitors, including the clinical candidate GS-9137 ( 2). A database search of small molecules using the quinolone 3-carboxylic acid pharmacophore model, followed by in vitro evaluation of selected hits in an assay specific to IN, resulted in the discovery of potential leads with diverse structural scaffolds useful for the design of second generation IN inhibitors.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Laith Q
authors.initials: LQ
authors.lastname: Al-Mawsawi
authors.forename: Zahrah
authors.initials: Z
authors.lastname: Zawahir
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D016208:Databases, Factual; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase