ArticleACS chemical biology2016
Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
18 citing papers in PubMed, 44 citations in OpenAlex.
- An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.Science translational medicine · 2024Article
- VSpipe-GUI, an Interactive Graphical User Interface for Virtual Screening and Hit Selection.International journal of molecular sciences · 2024Article
- Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration.Molecules (Basel, Switzerland) · 2023Article
- Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance.Journal of molecular biology · 2022Article
- Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.Journal of medicinal chemistry · 2021Article
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- Viral proteases: Structure, mechanism and inhibition.The Enzymes · 2021Article
- Mechanistic and Structural Features of PROTAC Ternary Complexes.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach.Computers in biology and medicine · 2020Article
- Article
- Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors.Critical reviews in biochemistry and molecular biology · 2019Review
- Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease.Structure (London, England : 1993) · 2018Article
- Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.ACS medicinal chemistry letters · 2018Article
- Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.Journal of medicinal chemistry · 2017Article
- Validation and correction of Zn-CysActa crystallographica. Section D, Structural biology · 2016Article
- 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
- Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively low susceptibility to resistance. MK-5172 has a P2-P4 macrocycle and a unique binding mode among current protease inhibitors where the P2 quinoxaline packs against the catalytic residues H57 and D81. However, the effect of macrocyclization on this binding mode is not clear, as is the relation between macrocyclization, thermodynamic stabilization, and susceptibility to the resistance mutation A156T. We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics, and experimental binding thermodynamics to the parent compound. We find that the "unique" binding mode of MK-5172 is conserved even when the P2-P4 macrocycle is removed or replaced with a P1-P3 macrocycle. While beneficial to decreasing the entropic penalty associated with binding, the constraint exerted by the P2-P4 macrocycle prevents efficient rearrangement to accommodate the A156T mutation, a deficit alleviated in the linear and P1-P3 analogs. Design of macrocyclic inhibitors against NS3/4A needs to achieve the best balance between exerting optimal conformational constraint for enhancing potency, fitting within the substrate envelope and allowing adaptability to be robust against resistance mutations.
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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.