TY - JOUR
T1 - Binding of GS-461203 and Its Halogen Derivatives to HCV Genotype 2a RNA Polymerase Drug Resistance Mutants
AU - Arba, Muhammad
AU - Wahyudi, Setyanto Tri
AU - Zubair, Muhammad Sulaiman
AU - Brunt, Dylan
AU - Singh, Mursalin
AU - Wu, Chun
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
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U2 - 10.3390/scipharm90020026
DO - 10.3390/scipharm90020026
M3 - Article
AN - SCOPUS:85129470753
SN - 0036-8709
VL - 90
JO - Scientia Pharmaceutica
JF - Scientia Pharmaceutica
IS - 2
M1 - 26
ER -