MEDI 95 |
| HIV-1 integrase (IN), one of the three viral-encoded enzymes required for the replication of the virus, is still an attractive though difficult target for the development of efficient anti-HIV drugs. Though a few promising clinical candidates exist, at present no anti-HIV drugs based on IN inhibition have been approved by the FDA. One of the reasons for the difficulties is the absence of crystal structures of the full-length enzyme and/or of the enzyme complexed with viral DNA. To address this, we had previously constructed models of full-length HIV-1 integrase complexed with models of viral and human DNA. We report here the results of virtual screening methods applied to one of these models. They yielded several ìM level inhibitors of the strand transfer reaction catalyzed by wild-type HIV-1 integrase, representing novel chemical structures. Additionally, we describe ligand-based development of HIV-1 integrase inhibitors, especially of strand transfer (ST) inhibitors based on known ST inhibitors with confirmed efficacy in patients. Based on the unique chemical features of these compounds as well as on features they have in common with the wider class of diketo acids IN inhibitors, two series of, in total, fourteen pharmacophores were developed, using the program Catalyst 4.11. We used these pharmacophores to search the ChemNavigator iResearch Library, an aggregated database of currently about 25 million purchasable screening samples, to select samples for purchase and subsequent assaying. We report on the status of these efforts. |
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |