Isaacs, D.Mikasi, S.G.Obasa, A.E.Ikomey, G.M.Shityakov, S.Cloete, R.Jacobs, G.B.2024-01-032024-01-032020-08-26Isaacs D, Mikasi SG, Obasa AE, et al. Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors. Viruses. 2020 Aug 26;12(9):936. doi: 10.3390/v12090936.https://doi.org/10.3390/v12090936https://www.mdpi.com/1999-4915/12/9/936https://infospace.mrc.ac.za/handle/11288/595326The 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.enAttribution 3.0 United Stateshttp://creativecommons.org/licenses/by/3.0/us/HIV-1diversityintegrasemolecular dockingmolecular modellingnaturally occurring polymorphisms.ArticleViruses