ArticleJournal of chemical theory and computation2013
Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design.
Article in Journal of chemical theory and computation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed.
- In Silico-Based Identification of Natural Inhibitors from Traditionally Used Medicinal Plants that can Inhibit Dengue Infection.Molecular biotechnology · 2025Article
- Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.Viruses · 2024Article
- Article
- Avoiding Drug Resistance in HIV Reverse Transcriptase.Chemical reviews · 2021Review
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- Viral proteases: Structure, mechanism and inhibition.The Enzymes · 2021Article
- Article
- Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies.Molecules (Basel, Switzerland) · 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
- Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.Journal of chemical theory and computation · 2017Article
- Exploring the Drug Resistance of HCV Protease.The journal of physical chemistry. B · 2017Article
- Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.Journal of medicinal chemistry · 2017Article
- Interdependence of Inhibitor Recognition in HIV-1 Protease.Journal of chemical theory and computation · 2017Article
- Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.Journal of the American Chemical Society · 2016Article
- Improving Viral Protease Inhibitors to Counter Drug Resistance.Trends in microbiology · 2016Review
- Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.ACS chemical biology · 2016Article
- Article
- Structural analysis of asunaprevir resistance in HCV NS3/4A protease.ACS chemical biology · 2014Article
- Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by NS3/4A; the drug resistant protease variants are no longer effectively inhibited by the competitive active site inhibitors but can still process the natural substrates with enough efficiency for viral survival. In previous works we have developed the "substrate envelope" hypothesis, which posits that inhibitors should be less susceptible to drug resistance if they better mimic the natural substrate molecular recognition features. In this work, we perform molecular dynamics simulations on four native substrates bound to NS3/4A and discover a clearly conserved dynamic substrate envelope. We show that the most severe drug resistance mutations in NS3/4A occur at residues that are outside the substrate envelope. Comparative analysis of three NS3/4A inhibitors reveals structural and dynamic characteristics of inhibitors that could lead to resistance. We also suggest inhibitor modifications to improve resistance profiles based on the dynamic substrate envelope. This study provides a general framework for guiding the development of novel inhibitors that will be more robust against resistance by mimicking the static and dynamic binding characteristics of natural substrates.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.