Understanding of the drug resistance mechanism of hepatitis C virus NS3/4A to paritaprevir due to D168N/Y mutations: A molecular dynamics simulation perspective
| Autor: | Thitiya Boonma, Thanyada Rungrotmongkol, Nadtanet Nunthaboot, Bodee Nutho |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cyclopropanes
0301 basic medicine Macrocyclic Compounds Proline medicine.drug_class Lactams Macrocyclic Hepatitis C virus medicine.medical_treatment Drug resistance Molecular Dynamics Simulation Viral Nonstructural Proteins medicine.disease_cause Antiviral Agents Biochemistry 03 medical and health sciences 0302 clinical medicine Structural Biology Drug Resistance Viral medicine Potency Sulfonamides NS3 Protease Chemistry Mechanism (biology) Organic Chemistry Intracellular Signaling Peptides and Proteins virus diseases Hydrogen Bonding Virology digestive system diseases Computational Mathematics 030104 developmental biology Paritaprevir 030220 oncology & carcinogenesis Mutation Thermodynamics Antiviral drug |
| Zdroj: | Computational Biology and Chemistry. 83:107154 |
| ISSN: | 1476-9271 |
| DOI: | 10.1016/j.compbiolchem.2019.107154 |
| Popis: | Hepatitis C virus (HCV) NS3/4A protease is an attractive target for the development of antiviral therapy. However, the evolution of antiviral drug resistance is a major problem for treatment of HCV infected patients. Understanding of drug-resistance mechanisms at molecular level is therefore very important for the guidance of further design of antiviral drugs with high efficiency and specificity. Paritaprevir is a potent inhibitor against HCV NS3/4A protease genotype 1a. Unfortunately, this compound is highly susceptible to the substitution at D168 in the protease. In this work, molecular dynamics simulations of paritaprevir complexed with wild-type (WT) and two mutated strains (D168 N and D168Y) were carried out. Due to such mutations, the inhibitor-protein hydrogen bonding between them was weakened and the salt-bridge network among residues R123, R155 and D168 responsible for inhibitor binding was disrupted. Moreover, the per-residue free energy decomposition suggested that the main contributions from key residues such as Q80, V132, K136, G137 and R155 were lost in the D168 N/Y mutations. These lead to a lower binding affinity of paritaprevir for D168 N/Y variants of the HCV NS3/4A protease, consistent with the experimental data. This detailed information could be useful for further design of high potency anti-HCV NS3/4A inhibitors. |
| Databáze: | OpenAIRE |
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