title: Beta-diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors.
abstract: HIV-1 Integrase (IN) is an essential enzyme for viral replication. The discovery of beta-diketo acids was crucial in the validation of IN as a legitimate target in drug discovery against HIV infection. In this study, we discovered a novel class of IN inhibitors using a 3D pharmacophore guided database search. We used S-1360 (1), the first IN inhibitor to undergo clinical trials, and three other analogues to develop a common feature pharmacophore hypothesis. Testing this four-featured pharmacophore against a multiconformational database of 150,000 structurally diverse small molecules yielded 1,700 compounds that satisfied the 3D query. Subsequently, all 1,700 compounds were docked into the active site of IN. On the basis of docking scores, Lipinski's rule-of-five, and structural novelty, 110 compounds were selected for biological screening. We found that compounds that contain both salicylic acid and a 2-thioxo-4-thiazolidinone (rhodanine) group (e.g. 5-13) showed significant inhibitory potency against IN, while the presence of either salicylic acid or a rhodanine group alone did not. Although some of the compounds containing only a salicylic acid showed inhibitory potency against IN, none of the compounds containing only rhodanine exhibited considerable potency. Of the 52 compounds reported in this study, 11 compounds (5, 6, 8, 10-13, 32-33, 51, and 53) inhibited 3'-processing or strand transfer activities of IN with IC(50) < or = 25 microM. This is the first reported use of S-1360 and its analogues as leads in developing a pharmacophore hypothesis for IN inhibition and for identification of new compounds with potent inhibition of this enzyme.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90089, USA.
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Omoshile
authors.initials: O
authors.lastname: Clement
authors.forename: Robert
authors.initials: R
authors.lastname: Shoemaker
authors.forename: Shizuko
authors.initials: S
authors.lastname: Sei
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005663:Furans; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012236:Rhodanine / Q000737:chemistry; D020156:Salicylic Acid / Q000737:chemistry; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014230:Triazoles
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; D019428:HIV Integrase Inhibitors; C451733:S 1360; D014230:Triazoles; D012236:Rhodanine; D019427:HIV Integrase; D020156:Salicylic Acid