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

Isaacs, D.
Mikasi, S.G.
Obasa, A.E.
Ikomey, G.M.
Shityakov, S.
Cloete, R.
Jacobs, G.B.
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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.
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Date
2020-08-26
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Publisher
MDPI
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Keywords
HIV-1,diversity,integrase,molecular docking,molecular modelling,naturally occurring polymorphisms.
Citation
Isaacs 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.
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