Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors

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dc.contributor.authorIsaacs, Darrenen_ZA
dc.contributor.authorMikasi, Sello Givenen_ZA
dc.contributor.authorObasa, Adetayo Emmanuelen_ZA
dc.contributor.authorIkomey, George Mondindeen_ZA
dc.contributor.authorShityakov, Sergeyen_ZA
dc.contributor.authorCloete, Rubenen_ZA
dc.contributor.authorJacobs, Graeme Brendonen_ZA
dc.date.accessioned2022-04-08T12:40:21Z
dc.date.available2022-04-08T12:40:21Z
dc.date.issued2020-08-26
dc.descriptionCITATION: Isaacs, Darren et al. 2020. Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors. Viruses, 12(9):936, doi:10.3390/v12090936.en_ZA
dc.descriptionThe original publication is available at: https://www.mdpi.com
dc.description.abstractENGLISH ABSTRACT: The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.en_ZA
dc.description.versionPublisher's version
dc.format.extent12 pagesen_ZA
dc.identifier.citationIsaacs, Darren et al. 2020. Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors. Viruses, 12(9):936, doi:10.3390/v12090936
dc.identifier.issn1999-4915 (online)
dc.identifier.otherdoi:10.3390/v12090936
dc.identifier.urihttp://hdl.handle.net/10019.1/124431
dc.language.isoen_ZAen_ZA
dc.publisherMDPI
dc.rights.holderAuthors retain copyright
dc.subjectHIV-1en_ZA
dc.subjectMolecular modelsen_ZA
dc.subjectViral genomesen_ZA
dc.subjectMolecular dockingen_ZA
dc.subjectNaturally occurring polymorphismsen_ZA
dc.subjectBacterial diversityen_ZA
dc.subjectIntegrase Inhibitorsen_ZA
dc.titleStructural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitorsen_ZA
dc.typeArticleen_ZA
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