TY  - JOUR
A1  - Isaacs, Darren
A1  - Mikasi, Sello Given
A1  - Obasa, Adetayo Emmanuel
A1  - Ikomey, George Mondinde
A1  - Shityakov, Sergey
A1  - Cloete, Ruben
A1  - Jacobs, Graeme Brendon
T1  - Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors
JF  - Viruses
N2  - 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.
KW  - integrase
KW  - naturally occurring polymorphisms
KW  - HIV-1
KW  - molecular modelling
KW  - molecular docking
KW  - diversity
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211170
SN  - 1999-4915
VL  - 12
IS  - 9
ER  -