Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study

• Published in: International journal of molecular sciences 2024-08, Vol.25 (15), p.8028
• Main Authors: Han, Di, Zhao, Fang, Chen, Yifan, Xue, Yiwei, Bao, Ke, Chang, Yuxiao, Lu, Jiarui, Wang, Meiting, Liu, Taigang, Gao, Qinghe, Cui, Wei, Xu, Yongtao
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzofurans - chemistry; Benzofurans - pharmacology; Binding Sites; Disease transmission; Energy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Genetic aspects; Genotype; Health aspects; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepacivirus - genetics; Hepatitis C; Hepatitis C virus; Humans; Hydrogen bonding; Hydrogen bonds; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Public health; RNA-Dependent RNA Polymerase; Simulation; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158028

The benzofuran core inhibitors , , , compound , and compound exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT , , , and NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position ( , , compound , and compound ) to the GT and NS5B polymerases exhibits different binding patterns compared to the binding to the GT and NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse β-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.