HCV Mutation Detail Information

Virus Mutation HCV Mutation M423I


Basic Characteristics of Mutations
Mutation Site M423I
Mutation Site Sentence To clarify the drug resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of NS5B polymerase (GT1b) and the receptor-ligand interactions during the binding process, a series of molecular simulation methods including molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for the wild-type (WT) and six mutant NS5B/GS-9669 complexes.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region NS5B
Standardized Encoding Gene NS5B
Genotype/Subtype 1b
Viral Reference -
Functional Impact and Mechanisms
Disease HCV Infection    
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment GS-9669
Location -
Literature Information
PMID 34093991
Title Insight into the drug resistance mechanisms of GS-9669 caused by mutations of HCV NS5B polymerase via molecular simulation
Author Han D,Wang H,Wujieti B,Zhang B,Cui W,Chen BZ
Journal Computational and structural biotechnology journal
Journal Info 2021 Apr 20;19:2761-2774
Abstract GS-9669 is a non-nucleos(t)ide inhibitor (NNI) binding to the thumb site II of the Hepatitis C virus (HCV) NS5B polymerase and has advanced into phase II trials. To clarify the drug resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of NS5B polymerase (GT1b) and the receptor-ligand interactions during the binding process, a series of molecular simulation methods including molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for the wild-type (WT) and six mutant NS5B/GS-9669 complexes. The calculated results indicate that the binding free energies of the mutant systems are less negative than that of the WT system, indicating that these mutations will indeed cause NS5B to produce different degrees of resistance to GS-9669. The mutation-induced drug resistances are mainly caused by the loss of binding affinities of Leu419 and Trp528 with GS-9669 or the formation of multiple solvent bridges. Moreover, the ASMD calculations show that GS-9669 binds to the thumb II sites of the seven NS5B polymerases in distinct pathways without any obvious energy barriers. Although the recognition methods and binding pathways are distinct, the binding processes of GS-9669 with the WT and mutant NS5B polymerases are basically controlled thermodynamically. This study clearly reveals the resistance mechanisms of GS-9669 caused by M423T/I/V, L419M, R422K, and I482L mutations of HCV NS5B polymerase and provides some valuable clues for further optimization and design of novel NS5B inhibitors.
Sequence Data -
Mutation Information
Note
Basic Characteristics of Mutations
  • Mutation Site: The specific location in a gene or protein sequence where a change occurs.
  • Mutation Level: The level at which a mutation occurs, including the nucleotide or amino acid level.
  • Mutation Type: The nature of the mutation, such as missense mutation, nonsense mutation, synonymous mutation, etc.
  • Gene/Protein/Region: Refers to the specific region of the virus where the mutation occurs. Including viral genes, viral proteins, or a specific viral genome region. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main
  • Gene/Protein/Region studied in the article is marked.
  • Genotype/Subtype: Refers to the viral genotype or subtype where the mutation occurs. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main Genotype/Subtype studied in the article is marked.
  • Viral Reference: Refers to the standard virus strain used to compare and analyze viral sequences.
Functional Impact and Mechanisms
  • Disease: An abnormal physiological state with specific symptoms and signs caused by viral infection.
  • Immune: The article focuses on the study of mutations and immune.
  • Target Gene: Host genes that viral mutations may affect.
Clinical and Epidemiological Correlations
  • Clinical Information: The study is a clinical or epidemiological study and provides basic information about the population.
  • Treatment: The study mentioned a certain treatment method, such as drug resistance caused by mutations. If the study does not specifically indicate the relationship between mutations and their correspondence treatment, the main treatment studied in the article is marked.
  • Location: The source of the research data.
Literature Information
  • Sequence Data: The study provides the data accession number.