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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.