Computer-assisted search and optimization of new integrase inhibitor of human immunodeficiency virus

Druzhilovsky D.S.1 , Filimonov D.A.1, Liao Ch.2, Peach M.2, Niclaus M.2, Poroikov V.V.1

1. Laboratory of Structure-Function Based Drug Design, Instutution of Russian Academy of Medical Sciences Institute of Biomedical Chemistry RAMS
2. National Cancer Institute, National Health Institute
Section: Experimental/Clinical Study
PubMed Id: 20017388
Year: 2009  Volume: 55  Issue: 5  Pages: 544-557
Finding and optimization of new HIV-1 integrase inhibitors is an important task due to the drawbacks of the existing antiretroviral therapy caused by the significant adverse effects, high cost of the treatment, and emerging resistance. In this study we used computer-assisted methods for finding and optimization of new HIV-1 integrase inhibitors blocking the 3'-processing reaction. Possibility of application of the specialized version of computer program PASS for searching original inhibitors of 3'-processing reaction among the commercially available samples of chemical compounds, belonging to a new chemical class, is shown. We compared the general pharmacological profiles calculated by PASS for the sets of original integrase inhibitors discovered in the study with those for known inhibitors published in literature. It was shown that the predicted average selectivity is close for the compounds from both sets, while the predicted adverse/toxic actions are less for the original compounds. Differences of pharmacological profiles of original compounds and known from literature inhibitors of 3'-processing pointed out to the essential novelty of our substances. Significantly less deviations from the recommended values for QikProp parameters, which characterized the ADME properties, have been observed for the original compounds than for the integrase inhibitors published in literature. Thus, one may come to the conclusion that the original compounds look more prospective comparing to the earlier known inhibitors of 3'-processing.
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Keywords: integrase of HIV-1, search and optimization, computer-assisted estimation, PASS, QikProp

Druzhilovsky, D. S., Filimonov, D. A., Liao, Ch., Peach, M., Niclaus, M., Poroikov, V. V. (2009). Computer-assisted search and optimization of new integrase inhibitor of human immunodeficiency virus. Biomeditsinskaya Khimiya, 55(5), 544-557.
This paper is also available as the English translation: 10.1134/S1990750810010087
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