Identification of HIV-1 integrase inhibitors based on a four-point pharmacophore

The rapid emergence of human immunodeficiency virus (HIV) strains resistant to available drugs implies that effective treatment modalities will requir e the use of a combination of drugs targeting different sites of the HIV li fe cycle. Because the virus cannot replicate without integration into a hos t chromosome, HIV-1 integrase (IN) is an attractive therapeutic target. Thu s, an effective IN inhibitor should provide additional benefit in combinati on chemotherapy. A four-point pharmacophore has been identified based on th e structures of quinalizarin and purpurin, which were found to be potent IN inhibitors using both a preintegration complex assay and a purified enzyme assay in vitro. Searching with this four-point pharmacophore in the 'open' part of the National Cancer Institute three-dimensional structure database produced 234 compounds containing the pharmacophore. Sixty of these compou nds were tested for their inhibitory activity against IN using the purified enzyme; 19 were found to be active against IN with IC50 values of less tha n 100 mu M, among which 10 had IC50 values of less than 10 mu M. These inhi bitors can further serve as leads, and studies are in progress to design no vel inhibitors based on the results presented in this study.