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 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.

First report of computational protein–ligand docking to evaluate susceptibility to HIV integrase inhibitors in HIV-infected Iranian patients

“…Conforming to the phylogenetic tree result, some new subtypes including CRF-01B and BF were introduced in Iranian patients for the first time. Of note, our data displayed RAMs found in our patients including V72I, I201V [ 53 , 54 ], M50I, R263K [ 3 ], and L74I/M, R263K, S230 N [ 54 ] were not specific for any subtype because they were revealed in different subtypes. Comparison of RAMS and NOPs between CRF 35-AD and other subtypes is shown in the Supplementary Table 11 .…”

“…It also contains a conserved DDE motif encompassing amino acids Asp64, Asp116, and Glu152 in the CCD necessary for drug binding and enzyme activity [ 2 ]. As a result of the drug resistance development across currently available drugs, WHO has put forth the use of INTIs: raltegravir (RAL) and elvitegravir (EVG) as the first-generation inhibitors, dolutegravir (DTG) and bictegravir (BIC), along with the late-phase clinically trialed cabotegravir (CAB), as the second-generation INTIs [ 3 ]. First-generation INTIs have a relatively low genetic barrier to resistance, whereas second-generation INTIs confer to a higher genetic barrier against RAMs [ 2 ].…”

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants

“…To avoid these susceptible mutations and those observed during virologic failure of DTG monotherapy, BIC is co-formulated with tenofovir alafenamide or emtricitabine (Acosta et al 2019 ; Wensing et al 2019 ). Isaacs et al ( 2020 ) conducted docking and EC50 experiments and derived a linear correlation between the inhibition constant values and experimental values for INSTIs, proposing that DTG and BIC are the most powerful IN inhibitors among all FDA-approved INSTIs.…”

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.…”