Binding of GS-461203 and Its Halogen Derivatives to HCV Genotype 2a RNA Polymerase Drug Resistance Mutants

Muhammad Arba, Setyanto Tri Wahyudi, Muhammad Sulaiman Zubair, Dylan Brunt, Mursalin Singh, Chun Wu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hepatitis C Virus (HCV) is reported to develop GS-461203 resistance because of multiple mutations within the RNA-dependent RNA Polymerase (RdRp) of HCV. The lack of a high-resolution structure of these RdRp mutants in complex with GS-461203 hinders efforts to understand the drug resistance. Here we decipher the binding differences of GS-461203 in the wild type and mutated systems T179A or M289L of HCV RdRp Genotype 2a using homology modeling, molecular docking, and molecular dynamics simulation. Key residues responsible for GS-461203 binding were identified to be Arg48, Arg158, Asp318, Asp319, and Asp220, and that mutations T179A or M289L have caused conformational changes of GS-461203 in the RdRp active site. The affinities of GS-461203 were reduced in T179A system, but it became slightly stronger in the M289L system. Furthermore, we designed two new analogues of GS-461203 which encouragingly induced more stable interactions than GS-461203, and thus resulted in much better binding energies. This present study reveals how a single mutation, T179A or M289L, will modulate GS-461203 binding in HCV RdRp Genotype 2a, while introducing two novel analogues to overcome the drug resistance which may be good candidate for further experimental verification.

Original languageEnglish (US)
Article number26
JournalScientia Pharmaceutica
Volume90
Issue number2
DOIs
StatePublished - Jun 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

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