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• W658842411 endingPage "e0128310" @default.
• W658842411 startingPage "e0128310" @default.
• W658842411 abstract "Understanding the HIV integrase protein and mechanisms of resistance to HIV integrase inhibitors is complicated by the lack of a full length HIV integrase crystal structure. Moreover, a lentiviral integrase structure with co-crystallised DNA has not been described. For these reasons, we have developed a structural method that utilizes free software to create quaternary HIV integrase homology models, based partially on available full-length prototype foamy virus integrase structures as well as several structures of truncated HIV integrase. We have tested the utility of these models in screening of small anti-integrase compounds using randomly selected molecules from the ZINC database as well as a well characterized IN:DNA binding inhibitor, FZ41, and a putative IN:DNA binding inhibitor, HDS1. Docking studies showed that the ZINC compounds that had the best binding energies bound at the IN:IN dimer interface and that the FZ41 and HDS1 compounds docked at approximately the same location in integrase, i.e. behind the DNA binding domain, although there is some overlap with the IN:IN dimer interface to which the ZINC compounds bind. Thus, we have revealed two possible locations in integrase that could potentially be targeted by allosteric integrase inhibitors, that are distinct from the binding sites of other allosteric molecules such as LEDGF inhibitors. Virological and biochemical studies confirmed that HDS1 and FZ41 share a similar activity profile and that both can inhibit each of integrase and reverse transcriptase activities. The inhibitory mechanism of HDS1 for HIV integrase seems to be at the DNA binding step and not at either of the strand transfer or 3' processing steps of the integrase reaction. Furthermore, HDS1 does not directly interact with DNA. The modeling and docking methodology described here will be useful for future screening of integrase inhibitors as well as for the generation of models for the study of integrase drug resistance." @default.
• W658842411 created "2016-06-24" @default.
• W658842411 creator A5029881635 @default.
• W658842411 creator A5042169672 @default.
• W658842411 creator A5045766366 @default.
• W658842411 creator A5066667610 @default.
• W658842411 creator A5087129093 @default.
• W658842411 date "2015-06-05" @default.
• W658842411 modified "2023-09-27" @default.
• W658842411 title "Structural Studies of the HIV-1 Integrase Protein: Compound Screening and Characterization of a DNA-Binding Inhibitor" @default.
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• W658842411 doi "https://doi.org/10.1371/journal.pone.0128310" @default.
• W658842411 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4457863" @default.
• W658842411 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26046987" @default.
• W658842411 hasPublicationYear "2015" @default.
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