ArticleJournal of molecular biology2011
Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.
Article in Journal of molecular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- The substrate envelope strategy: Structural basis for resistance mitigation in antiviral drug design.Pharmaceutical science advances · 2026Review
- Fluorinated HIV-1 protease inhibitors containing chiral hydroxyethylbenzene and indanol as P2' ligands with potent activity against drug-resistant variants.European journal of medicinal chemistry · 2026Article
- Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.Viruses · 2024Article
- Article
- Protein-Protein Interaction Studies Using Molecular Dynamics Simulation.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease.Protein science : a publication of the Protein Society · 2022Article
- Elasticity-Associated Functionality and Inhibition of the HIV Protease.Advances in experimental medicine and biology · 2022Article
- Review
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- A synergy of activity, stability, and inhibitor-interaction of HIV-1 protease mutants evolved under drug-pressure.Protein science : a publication of the Protein Society · 2021Article
- Viral proteases: Structure, mechanism and inhibition.The Enzymes · 2021Article
- Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.Journal of medicinal chemistry · 2020Article
- Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.ACS chemical biology · 2019Article
- Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.Critical reviews in biochemistry and molecular biology · 2019Review
- Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics.Scientific reports · 2018Article
- HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites.Journal of molecular biology · 2018Article
- A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease.Acta crystallographica. Section D, Structural biology · 2018Article
- Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.Journal of chemical theory and computation · 2017Article
- Inference of Epistatic Effects Leading to Entrenchment and Drug Resistance in HIV-1 Protease.Molecular biology and evolution · 2017Article
- Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side.Journal of virology · 2017Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate envelope, because these regions are crucial for drug binding but not for substrate recognition. We extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. We simulated the molecular dynamics of seven PR-substrate complexes to estimate the conformational flexibility of the bound substrates. Interdependence of substrate-protease interactions might compensate for variations in cleavage-site sequences and explain how a diverse set of sequences are recognized as substrates by the same enzyme. This diversity might be essential for regulating sequential processing of substrates. We define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance.
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