β-Diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 Integrase inhibitors

HIV-1 Integrase (IN) is an essential enzyme for viral replication. The discovery of β-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 1700 compounds that satisfied the 3D query. Subsequently, all 1700 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, whil...