Main Article Content


Hepatitis C Virus (HCV) is one of the infectious diseases that has posed a serious threat to global public health for the past few decades. HCV is an RNA virus that infects the human liver and can lead to chronic liver damage, cirrhosis, and even liver cancer. Treatment for HCV infection has made rapid advancements in recent years, particularly with the development of more effective antiviral drugs. One of the drugs used in HCV therapy is dasabuvir. Dasabuvir is an RNA-dependent RNA polymerase (RdRp) inhibitor that functions to inhibit the replication of the HCV virus. The RdRp enzyme in HCV is represented by NS5B, and dasabuvir specifically targets this enzyme. Several reports have revealed mutations in HCV NS5B due to the use of dasabuvir. This study conducted a computational mutation analysis on NS5B of HCV resulting from dasabuvir usage. The research findings indicate that mutations in the HCV polymerase induced by dasabuvir usage lead to changes in dasabuvir's conformation and binding energy. Some mutations decrease binding energy, such as mutations C316N, C451S, and N411S. However, on the other hand, there are mutations that increase binding energy, such as M414V, A553V, and C445F. The decrease in binding energy is supported by increased hydrogen bonding interactions with Asp318, Gln446, and Tyr448, as well as the formation of new hydrogen bonds, such as hydrogen bonding with Ser288 in C451S and Arg200 in C451S. Meanwhile, the increase in binding energy is supported by decreased binding interactions with Asp318 and pi-pi interactions with Phe193. Hydrogen bonding with Asn291 also decreases, as seen in A553V, and is even lost in C445F. Future work will be devoted for designing new dasabuvir derivatives which having better affinited to NS5B of HCV.


RNA-dependent RNA Polymerase (RdRp) Mutation Hepatitis C Virus Dasabuvir Drug resistance

Article Details

How to Cite
Arba, M., & Wahyudi, S. T. (2024). Effect of Mutation of RNA-dependent RNA Polymerase (RdRp) of Hepatitis C Virus on Affinities of Dasabuvir: Computational Study: Pengaruh Mutasi RNA-dependent RNA polymerase (RdRp) pada Virus Hepatitis C terhadap Afinitas Dasabuvir: Kajian Komputasi. Jurnal Farmasi Galenika (Galenika Journal of Pharmacy) (e-Journal), 10(1), 1-12.


  1. Akaberi, D., Bergfors, A., Kjellin, M., Kameli, N., Lidemalm, L., Kolli, B., . . . Lennerstrand, J. (2018). Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by the in silico approach. Infection Ecology & Epidemiology, 8(1), 1528117. doi:10.1080/20008686.2018.1528117
  2. Arba, M., Ningsih, A. S., Bande, L. O. S., Wahyudi, S. T., Bui-Linh, C., Wu, C., & Karton, A. (2023). Computational insights into the binding of pimodivir to the mutated PB2 subunit of the influenza A virus. Molecular Simulation, 1-13. doi:10.1080/08927022.2023.2210690
  3. Arba, M., Wahyudi, S. T., Zubair, M. S., Brunt, D., Singh, M., & Wu, C. (2022). Binding of GS-461203 and Its Halogen Derivatives to HCV Genotype 2a RNA Polymerase Drug Resistance Mutants. Scientia Pharmaceutica, 90(2). doi:10.3390/scipharm90020026
  4. Bailey, A. G., & Lowe, C. P. (2009). MILCH SHAKE: An Efficient Method for Constraint Dynamics Applied to Alkanes. Journal of Computational Chemistry, 30(15), 2485-2493. doi:10.1002/jcc.21237
  5. Banks, J. L., Beard, H. S., Cao, Y., Cho, A. E., Damm, W., Farid, R., . . . Levy, R. M. (2005). Integrated Modeling Program, Applied Chemical Theory (IMPACT). Journal of Computational Chemistry, 26(16), 1752-1780. doi:
  6. Bukh, J. (2016). The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. Journal of Hepatology, 65(1), S2-S21. doi:10.1016/j.jhep.2016.07.035
  7. Cento, V., Chevaliez, S., & Perno, C. F. (2015). Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS, 10(5), 381-389. doi:10.1097/COH.0000000000000177
  8. Chen, Z.-w., Li, H., Ren, H., & Hu, P. (2016). Global prevalence of pre-existing HCV variants resistant to direct-acting antiviral agents (DAAs): mining the GenBank HCV genome data. Scientific Reports, 6(1), 20310. doi:10.1038/srep20310
  9. Eltahla, A. A., Luciani, F., White, P. A., Lloyd, A. R., & Bull, R. A. (2015). Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance. Viruses, 7(10), 5206-5224. doi:10.3390/v7102868
  10. Harder, E., Damm, W., Maple, J., Wu, C., Reboul, M., Xiang, J. Y., . . . Friesner, R. A. (2016). OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. Journal of Chemical Theory and Computation, 12(1), 281-296. doi:10.1021/acs.jctc.5b00864
  11. Ikeguchi, M. (2004). Partial rigid-body dynamics in NPT, NPAT and NP gamma T ensembles for proteins and membranes. Journal of Computational Chemistry, 25(4), 529-541. doi:10.1002/jcc.10402
  12. Jorgensen, W. L., Maxwell, D. S., & TiradoRives, J. (1996). Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. Journal of the American Chemical Society, 118(45), 11225-11236. doi:10.1021/ja9621760
  13. Kati, W., Koev, G., Irvin, M., Beyer, J., Liu, Y., Krishnan, P., . . . Collins, C. (2015). In Vitro Activity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor. Antimicrobial agents and chemotherapy, 59(3), 1505-1511. doi:10.1128/aac.04619-14
  14. Kohli, A., Shaffer, A., Sherman, A., & Kottilil, S. (2014). Treatment of Hepatitis C A Systematic Review. Jama-Journal of the American Medical Association, 312(6), 631-640. doi:10.1001/jama.2014.7085
  15. Li, J., Abel, R., Zhu, K., Cao, Y., Zhao, S., & Friesner, R. A. (2011). The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins, 79(10), 2794-2812. doi:10.1002/prot.23106
  16. Patel, D. C., Hausman, K. R., Arba, M., Tran, A., Lakernick, P. M., & Wu, C. (2022). Novel inhibitors to ADP ribose phosphatase of SARS-CoV-2 identified by structure-based high throughput virtual screening and molecular dynamics simulations. Computers in Biology and Medicine, 140, 105084. doi:
  17. Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des, 27(3), 221-234. doi:10.1007/s10822-013-9644-8
  18. Schoenfeld, R. C., Bourdet, D. L., Brameld, K. A., Chin, E., de Vicente, J., Fung, A., . . . Zhao, J. (2013). Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B. Journal of Medicinal Chemistry, 56(20), 8163-8182. doi:10.1021/jm401266k
  19. Sorbo, M. C., Cento, V., Di Maio, V. C., Howe, A. Y. M., Garcia, F., Perno, C. F., & Ceccherini-Silberstein, F. (2018). Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. Drug Resistance Updates, 37, 17-39. doi:
  20. Stuart, S. J., Zhou, R., & Berne, B. J. (1996). Molecular dynamics with multiple time scales: The selection of efficient reference system propagators. The Journal of Chemical Physics, 105(4), 1426-1436. doi:10.1063/1.472005