Abstract
Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4′-stilbenedicarboxylate-alt–maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C). Homology modeling was used to create models of the gp120 proteins. Using monomers of the gp120 protein, we applied extensive molecular dynamics simulations to obtain dominant morphologies that represent a variety of open-closed states of the V3 loop to examine the interaction of 112 ligands of the repeating units of DCSti-alt-MA docked to the V3 loop and surrounding residues. Using the distance between the V1/V2 and V3 loops of gp120 as a metric, we revealed through MD simulations that gp120 from the lab-adapted strains (BaL and IIIb), which are more susceptible to inhibition by DCSti-alt-MA, clearly transitioned to the closed state in one replicate of each simulation set, whereas none of the replicates from the Tier II strains (92UG037 and JR-CSF) did so. Docking repeat unit microspecies to the gp120 protein before and after MD simulation enabled identification of residues that were key for binding. Notably, only a few residues were found to be important for docking both before and after MD simulation as a result of the conformational heterogeneity provided by the simulations. Consideration of the residues that were consistently involved in interactions with the ligand revealed the importance of both hydrophilic and hydrophobic moieties of the ligand for effective binding. The results also suggest that polymers of DCSti-alt-MA with repeating units of different configurations may have advantages for therapeutic efficacy.
Highlights
Over 37 million people worldwide are living with HIV, with an additional 7000 new infections daily [1]
All homology models, including the modified crystal structure, were energy minimized in Molecular Operating Environment (MOE) [45] with Amber12EHT [46] parameters and validated with Ramachandran plots [47], ANOLEA [48], and QMEAN [49] (Figures C-H in S1 File) by using RAMPAGE [47] and the SwissModel [50] suite of tools
Multiple approaches are being investigated to identify therapeutics that will prevent HIV infection. Among these approaches is the search for HIV entry inhibitors, those compounds that can prevent the fusion and entry of HIV into host cells
Summary
Over 37 million people worldwide are living with HIV, with an additional 7000 new infections daily [1]. In the absence of a vaccine and with the continuing spread of the virus, a pressing need remains for new preventative strategies, including microbicides [2] Because they inhibit viral entry and are biocompatible, polyanions have been tested as gel-formulated microbicides [3, 4]. Polyanions, such as commercially available PRO2000 and dextran sulfate, have shown excellent results in preclinical, Phase I, and Phase II clinical trials; Phase III clinical trials have been largely unsuccessful [3, 5,6,7]. As current microbicides under development are primarily reverse transcriptase and integrase inhibitors [7] and do not include polyanionic entry inhibitors, one might expect that a well-designed polyanion could overcome the pitfalls of previous polymers to provide a low-cost agent to add to the microbicidal cocktail
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