Identification of HIV-1 integrase inhibitors via three-dimensional database searching using ASV and HIV-1 integrases as targets

Integration of viral DNA. into the host cell genome is a critical step in t he life cycle of HIV. This essential reaction is catalyzed by integrase (IN ) through two steps, 3'-processing and DNA strand transfer. Integrase is an attractive target for drug design because there is no known cellular analo gue and integration is essential for successful replication of HIV. A compu tational three-dimensional (3-D) database search was used to identify novel HIV-1 integrase inhibitors. Starting from the previously identified Y3 (4- acetylamino-5-hydroxynaphthalene-2,7-disulfonic acid) binding site on the a vian sarcoma virus integrase (ASV IN), a preliminary search of all compound s in the nonproprietary, open part of the National Cancer Institute 3-D dat abase yielded a collection of 3100 compounds. A more rigorous scoring metho d was used to rescreen the 3100 compounds against both ASV IN and HIV-1 IN. Twenty-two of those compounds were selected for inhibition assays against HIV-1 IN. Thirteen of the 22 showed inhibitory activity against HIV-1 IN at concentrations less than 200 mu M and three of them showed antiviral activ ities in HIV-1 infected CEM cells with effective concentrations (EC50) rang ing from 0.8 to 200 mu M. Analysis of the computer-generated binding modes of the active compounds to HIV-1 IN showed that simultaneous interaction wi th the Y3 site and the catalytic site is possible. In addition, interaction s between the active compounds and the flexible loop involved in the bindin g of DNA by IN are indicated to occur. The structural details and the uniqu e binding motif between the HIV-1 IN and its inhibitors identified in the p resent work may contribute to the future development of IN inhibitors. (C) 2000 Elsevier Science Ltd. All rights reserved.