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Bioorg Med Chem Lett. 2012 May 1;22(9):3109-14. doi: 10.1016/j.bmcl.2012.03.064. Epub 2012 Mar 21.

Discovery of small molecule HIV-1 integrase dimerization inhibitors.

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Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.


Human immunodeficiency virus-1 integrase (HIV-1 IN) inserts the viral DNA into host cell chromatin in a multistep process. This enzyme exists in equilibrium between monomeric, dimeric, tetrameric and high order oligomeric states. However, monomers of IN are not capable of supporting its catalytic functions and the active form has been shown to be at least a dimer. As a consequence, the development of inhibitors targeting IN dimerization constitutes a promising novel antiviral strategy. In this work, we successfully combined different computational techniques in order to identify small molecule inhibitors of IN dimerization. Additionally, a novel AlphaScreen-based IN dimerization assay was used to evaluate the inhibitory activities of the selected compounds. To the best of our knowledge, this study represents the first successful virtual screening and evaluation of small molecule HIV-1 IN dimerization inhibitors, which may serve as attractive hit compounds for the development of novel anti-HIV.

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