Analysis of the Resistance of Hepatitis C Virus NS5B Polymerase Inhibitors via Docking and Molecular Dynamics Simulation
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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Tanaporn Uengwetwanit1, Dina Robaa1, Wolfgang Sippl2
1Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany phone: +49-345-55-25040; fax: +49-345-55-27355.
Abstract:
In this work, we examined how known single point mutations (P495S, P495L, P495A, P496A, P496S and V499A) in Hepatitis C virus NS5B polymerase influence the binding of benzimidazole-5-carboxamide derivatives which are potent NS5B inhibitors. Docking and molecular dynamics simulations were performed to analyze the binding of the inhibitors to the wild-type and mutant enzymes. Binding free energy calculations (MM-GB/SA method) and analyzing the decomposed binding free energy of individual residues were able to explain the differences in the inhibitory potency of the compounds at wild-type and mutant enzymes and hence account for the appearance of resistance of mutant enzymes to the studied inhibitors. The obtained results were found to be in agreement with the known experimental data.
