ArticleViruses2021
Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation.
Article in Viruses, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Damaging the conical morphology of HIV-1 capsid by targeting the FG-binding pocket and disfavoring pentameric subunits needed for core closure.bioRxiv : the preprint server for biology · 2026Article
- Recurrent and novel evolutionary pathways drive in vitro HIV-1 lenacapavir resistance with diverse phenotypic consequences.Nature communications · 2026Article
- Delineating Structural Functionalities of Lenacapavir Amenable to Modifications for Targeting Emerging Drug-Resistant HIV‑1 Capsid Variants.ACS medicinal chemistry letters · 2025Article
- Considerations for capsid-targeting antiretrovirals in pre-exposure prophylaxis.Trends in molecular medicine · 2025Review
- IP6, PF74 affect HIV-1 capsid stability through modulation of hexamer-hexamer tilt angle preference.Biophysical journal · 2025Article
- State of the ART (antiretroviral therapy): Long-acting HIV-1 therapeutics.Global health & medicine · 2024Review
- Article
- Elucidating the molecular determinants for binding modes of a third-generation HIV-1 integrase strand transfer inhibitor: Importance of side chain and solvent reorganization.bioRxiv : the preprint server for biology · 2023Article
- Targeting the HIV-1 and HBV Capsids, an EnCore.Viruses · 2023Article
- Between Protein Fold and Nucleophile Identity: Multiscale Modeling of the TEV Protease Enzyme-Substrate Complex.ACS omega · 2022Article
- Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.Journal of computer-aided molecular design · 2022Article
- HIV Capsid Protein Genetic Diversity Across HIV-1 Variants and Impact on New Capsid-Inhibitor Lenacapavir.Frontiers in microbiology · 2022Article
- Rotten to the core: antivirals targeting the HIV-1 capsid core.Retrovirology · 2021Review
- HIV-1 capsid variability: viral exploitation and evasion of capsid-binding molecules.Retrovirology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein-ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein-ligand steric clash, the I66 side chain in the M66I-GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein-ligand interaction that is largely responsible for the drug resistance against GS-6207.
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