Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

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 catalyses 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). In this study, we applied computational methods of molecular modelling and docking to analyse the effect of NOPs on the full-length IN structure and INSTI binding. We identified 16 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 effect on INSTI binding. INSTIs displayed similar binding affinities to each IN structure. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment naïve populations. This study supports the use of second-generation INSTI DTG as part of first-line combination antiretroviral therapy (cART) regimens, due to DTG possessing a stronger genetic barrier to the emergence of drug resistance.

Ugonin J Acts as a SARS-CoV-2 3C-like Protease Inhibitor and Exhibits Anti-inflammatory Properties

“…As for Lu, Kae, and Ikae, these compounds mainly interacted with the residues in subsites S2 and S4 via van der Waals forces. To validate the molecular docking methodology, linear regression analysis was performed to characterize the relationship between the experimental data (e.g., IC 50 values) and the binding energy from molecular modeling ( Isaacs et al, 2020 ). The linear relationship between the IC 50 values and the binding energy from GEMDOCK and molecular dynamics (MD) simulation have an R-square value of 0.8843 and 0.9096, respectively, as shown in Supplementary Figure S1 .…”

Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations

“…Our previous studies found low level of RAMSs against INSTIs (21). Our recent studies on CRF02_AG, reported that NOPs can have an effect on DTG binding with or without combination of primary mutation (19,24,28). In the current, study we analysed the CRF02_AG IN gene sequences for the presence of polymorphic and non-polymorphic mutations.…”

“…There is limited information available on the IN structure of CRF02_AG (19). There is henceforth a need to continue monitoring patients to identify additional RAMs and polymorphic mutations that might affect the genetic barrier to the development of RAMs against INSTI (8).…”

Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations

“…In a recent study on CRF02_AG IN, we reported that accessory mutations can impact the binding of DTG with or without combination of primary resistance mutations [ 32 , 36 ]. In this study we analysed the CRF02_AG IN gene sequences for the presence of polymorphic and non-polymorphic mutations.…”