Main Article Content

Abstract

Hepatitis C Virus (HCV) is a world health problem. HCV infection is initiated by various structural and non-structural proteins. The HCV NS3 protein has an important function in viral replication. The N-terminal domain of NS3 acts as a protease to process most of the viral polypeptides. NS3 also acts as an RNA helicase and NTPase and triggers liver fibrosis which accelerates the development of liver disease. Thus, this study aims to provide information on potential new antiviral candidates against HCV that target the NS3 protein. This study was conducted in-silico with a ligand-based and structure-based pharmacophore model to the cavity of the active protein site generated after virtual screening and molecular docking. The results of this study showed that three compounds, namely stigmasterol, gamma-mangostin, and erycristagallin, were found as HCV antiviral candidates that target the NS3 protein with a lower binding affinity than the native ligand. The binding energy of each compound is -9.23 Kcal/mol, -8.58 Kcal/mol, and -8.17 Kcal/mol. Based on ADMET analysis, the three compounds have high absorption in the small intestine. The cytotoxicity analysis of stigmasterol compounds is not potentially mutagenic, and the LD50 value of stigmasterol is also lower than other compounds.

Keywords

HCV NS3 molecular docking pharmacophore modeling

Article Details

How to Cite
1.
Rahayu R, Erlina L, Ratnoglik SL, Yasmon A, Fadilah, Paramita RI. Identification of Antiviral Compounds against Hepatitis C Virus (HCV) targeting NS3 Protein by Pharmacophore Modeling, Molecular Docking, and ADMET Approach. EKSAKTA [Internet]. 2023Dec.30 [cited 2024Jun.21];23(04):523-36. Available from: https://eksakta.ppj.unp.ac.id/index.php/eksakta/article/view/448

References

  1. WHO (2021). Global progress report on HIV, viral hepatitis and sexually transmitted infections. WHO, 53:9.
  2. Huang, H.C. (2020). Direct-acting antivirals: The answer to hepatitis C virus reactivation after organ transplantation. Journal of the Chinese Medical Association : JCMA, 83(4), 319–320.
  3. Caputo, V., Diotti, R. A., Boeri, E., Hasson, H., Sampaolo, M., Criscuolo, E., Bagaglio, S., Messina, E., Uberti-Foppa, C., Castelli, M., Burioni, R., Mancini, N., Clementi, M., & Clementi, N. (2020). Detection of low-level HCV variants in DAA treated patients: comparison amongst three different NGS data analysis protocols. Virology Journal, 17(1), 103.
  4. Rossetti, B., Paglicci, L., Di Maio, V. C., Cassol, C., Barbaliscia, S., Paolucci, S., Bruzzone, B., Coppola, N., Montagnani, F., Micheli, V., Monno, L., Zanelli, G., Santantonio, T., Cuomo, N., Caudai, C., Zazzi, M., Ceccherini-Silberstein, F., & On Behalf Of The Hcv Virology Italian Resistance Network Vironet, C. (2021). Prevalence of resistance-associated substitutions to NS3, NS5A and NS5B inhibitors at DAA-failure in hepatitis C virus in Italy from 2015 to 2019. Le Infezioni in Medicina, 29(2), 242–251.
  5. Ramirez, S., Fernandez-Antunez, C., Mikkelsen, L. S., Pedersen, J., Li, Y.-P., & Bukh, J. (2020). Cell Culture Studies of the Efficacy and Barrier to Resistance of Sofosbuvir-Velpatasvir and Glecaprevir-Pibrentasvir against Hepatitis C Virus Genotypes 2a, 2b, and 2c. Antimicrobial Agents and Chemotherapy, 64(3).
  6. Reddy, U. B., Tandon, H., Pradhan, M. K., Adhikesavan, H., Srinivasan, N., Das, S., & Jayaraman, N. (2020). Potent HCV NS3 Protease Inhibition by a Water-Soluble Phyllanthin Congener. ACS Omega, 5(20), 11553–11562.
  7. Pascut, D., Hoang, M., Nguyen, N. N. Q., Pratama, M. Y., & Tiribelli, C. (2021). HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers, 13(10).
  8. Goto, K., Roca Suarez, A. A., Wrensch, F., Baumert, T. F., & Lupberger, J. (2020). Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. International Journal of Molecular Sciences, 21(9).
  9. Patil, V. S., Harish, D. R., Vetrivel, U., Roy, S., Deshpande, S. H., & Hegde, H. V. (2022). Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. Molecules (Basel, Switzerland), 27(3).
  10. Bachar, S. C., Mazumder, K., Bachar, R., Aktar, A., & Al Mahtab, M. (2021). A Review of Medicinal Plants with Antiviral Activity Available in Bangladesh and Mechanistic Insight Into Their Bioactive Metabolites on SARS-CoV-2, HIV and HBV. Frontiers in Pharmacology, 12.
  11. Elgoud Said, A. A., Afifi, A. H., Ali, T. F. S., Samy, M. N., Abdelmohsen, U. R., Fouad, M. A., & Attia, E. Z. (2021). NS3/4A helicase inhibitory alkaloids from Aptenia cordifolia as HCV target. RSC Advances, 11(52), 32740–32749.
  12. Anwar, T., Kumar, P., & Khan, A. U. (2021). Molecular Docking for Computer-Aided Drug Design. In M. S. Coumar (Ed.), Molecular Docking for Computer-Aided Drug Design. Academic Press.
  13. Medina-Franco, J. L. (2021). Grand Challenges of Computer-Aided Drug Design: The Road Ahead. Frontiers in Drug Discovery, 1.
  14. Bajorath, J. (2022). Deep Machine Learning for Computer-Aided Drug Design. Frontiers in Drug Discovery, 2.
  15. Pinzi, L., & Rastelli, G. (2019). Molecular Docking: Shifting Paradigms in Drug Discovery. International Journal of Molecular Sciences, 20(18).
  16. Han, Y., Zhang, J., Hu, C. Q., Zhang, X., Ma, B., & Zhang, P. (2019). In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities. Frontiers in Pharmacology, 10, 434.
  17. Tijjani, H., Olatunde, A., Adegunloye, A. P., & Ishola, A. A. (2022). Chapter 14 - In silico insight into the interaction of 4-aminoquinolines with selected SARS-CoV-2 structural and nonstructural proteins. In C. B. T.-C. D. D. Egbuna (Ed.), Drug Discovery Update (pp. 313–333). Elsevier.
  18. Tyagi, R., Singh, A., Chaudhary, K. K., & Yadav, M. K. (2022). Pharmacophore modeling and its applications. In D. B. Singh & R. K. Pathak (Eds.), Bioinformatics (pp. 269–289). Academic Press.
  19. Vyas, V. K., Qureshi, G., Dayani, H., Jha, A., & Ghate, M. (2020). Pharmacophore-based identification and in vitro validation of apoptosis inducers as anticancer agents. SAR and QSAR in Environmental Research, 31(11), 869–881.
  20. Mejías, C., & Guirola, O. (2019). Pharmacophore model of immunocheckpoint protein PD-L1 by cosolvent molecular dynamics simulations. Journal of Molecular Graphics & Modelling, 91, 105–111.
  21. Opo, F. A. D. M., Rahman, M. M., Ahammad, F., Ahmed, I., Bhuiyan, M. A., & Asiri, A. M. (2021). Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein. Scientific Reports, 11(1), 4049.
  22. Vázquez, J., López, M., Gibert, E., Herrero, E., & Luque, F. J. (2020). Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches. Molecules (Basel, Switzerland), 25(20).
  23. LaPlante, S. R., Padyana, A. K., Abeywardane, A., Bonneau, P., Cartier, M., Coulombe, R., Jakalian, A., Wildeson-Jones, J., Li, X., Liang, S., McKercher, G., White, P., Zhang, Q., & Taylor, S. J. (2014). Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus. Journal of Medicinal Chemistry, 57(5), 2074–2090.
  24. Giordano, D., Biancaniello, C., Argenio, M. A., & Facchiano, A. (2022). Drug Design by Pharmacophore and Virtual Screening Approach. Pharmaceuticals (Basel, Switzerland), 15(5).
  25. Proekt, A., & Hemmings, H. C. (2019). Pharmacology and Physiology fo. In H. C. Hemmings & T. D. Egan (Eds.), Pharmacology and Physiology for Anesthesia (Second Edition). Elsevier.
  26. Cazals, F., & Tetley, R. (2019). Characterizing molecular flexibility by combining least root mean square deviation measures. Proteins, 87(5), 380–389.
  27. Xue, Q., Liu, X., Russell, P., Li, J., Pan, W., Fu, J., & Zhang, A. (2022). Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock. Ecotoxicology and Environmental Safety, 233, 113323.
  28. Hazarika, L., Sen, S., & Doshi, J. (2021). Molecular docking analysis of arjunolic acid from Terminalia arjuna with a coronary artery disease target APOE4. Bioinformation, 17(11), 949–958.
  29. Owoloye, A. J., Ligali, F. C., Enejoh, O. A., Musa, A. Z., Aina, O., Idowu, E. T., & Oyebola, K. M. (2022). Molecular docking, simulation and binding free energy analysis of small molecules as Pf HT1 inhibitors. PLoS ONE, 17(8), 1–18.
  30. Goswami, M., Priya, Jaswal, S., Gupta, G. Das, & Verma, S. K. (2023). A comprehensive update on phytochemistry, analytical aspects, medicinal attributes, specifications and stability of stigmasterol. Steroids, 196, 109244.
  31. Soekamto, N. H., Firdaus, Ahmad, F., & Appa, F. E. (2019). Potential of stigmasterol from EtOAc extract Melochia umbellata (Houtt) Stapf var. Visenia as Dengue Antivirus. Journal of Physics: Conference Series, 1341(3), 32044.
  32. Bakrim, S., Benkhaira, N., Bourais, I., Benali, T., Lee, L.-H., El Omari, N., Sheikh, R. A., Goh, K. W., Ming, L. C., & Bouyahya, A. (2022). Health Benefits and Pharmacological Properties of Stigmasterol. Antioxidants (Basel, Switzerland), 11(10).
  33. Alawode, T. T., Lajide, L., Olaleye, M., & Owolabi, B. (2021). Stigmasterol and β-Sitosterol: Antimicrobial Compounds in the Leaves of Icacina trichantha identified by GC–MS. Beni-Suef University Journal of Basic and Applied Sciences, 10(1), 80.
  34. Marliyana, S. D., Wibowo, F. R., Handayani, D. S., Kusumaningsih, T., Suryanti, V., Firdaus, M., & Annisa, E. N. (2021). Stigmasterol and Stigmasterone from Methanol Extract of Calophyllum soulattri Burm. F. Stem Bark. Jurnal Kimia Sains Dan Aplikasi, 24(4), 108-113.
  35. Patil, P., Agrawal, M., Almelkar, S., Jeengar, M. K., More, A., Alagarasu, K., Kumar, N. V, Mainkar, P. S., Parashar, D., & Cherian, S. (2021). In vitro and in vivo studies reveal α-Mangostin, a xanthonoid from Garcinia mangostana, as a promising natural antiviral compound against chikungunya virus. Virology Journal, 18(1), 47.
  36. Ansori, A., Kharisma, V., Parikesit, A. A., Dian, F., Probojati, R., Rebezov, M., Scherbakov, P., Burkov, P. V, Zhdanova, G., Mikhalev, A., Antonius, Y., Pratama, M., Sumantri, N., Sucipto, T., & Zainul, R. (2022). Bioactive Compounds from Mangosteen (Garcinia mangostana L.) as an Antiviral Agent via Dual Inhibitor Mechanism against SARSCoV- 2: An In Silico Approach. Pharmacognosy Journal, 14, 85–90.
  37. Kumar, A., Lingadurai, S., Jain, A., & Barman, N. R. (2010). Erythrina variegata Linn: A review on morphology, phytochemistry, and pharmacological aspects. Pharmacognosy Reviews, 4(8), 147–152.
  38. Sadgrove, N. J., Oliveira, T. B., Khumalo, G. P., Vuuren, S. F. van, & van Wyk, B.-E. (2020). Antimicrobial Isoflavones and Derivatives from Erythrina (Fabaceae): Structure Activity Perspective (Sar & Qsar) on Experimental and Mined Values Against Staphylococcus Aureus. Antibiotics (Basel, Switzerland), 9(5).
  39. Syahdi, R. R., Mun’im, A., Suhartanto, H., & Yanuar, A. (2012). Virtual screening of Indonesian herbal database as HIV-1 reverse transcriptase inhibitor. Bioinformation, 8(24), 1206–1210.
  40. Guan, L., Yang, H., Cai, Y., Sun, L., Di, P., Li, W., Liu, G., & Tang, Y. (2019). ADMET-score - a comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm, 10(1), 148–157.
  41. Lagorce, D., Douguet, D., Miteva, M. A., & Villoutreix, B. O. (2017). Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. Scientific Reports, 7(1), 46277.
  42. Flores-Holguín, N., Frau, J., & Glossman-Mitnik, D. (2021). In Silico Pharmacokinetics, ADMET Study and Conceptual DFT Analysis of Two Plant Cyclopeptides Isolated From Rosaceae as a Computational Peptidology Approach. Frontiers in Chemistry, 9.
  43. Egbuna, C., Patrick-Iwuanyanwu, K. C., Onyeike, E. N., Uche, C. Z., Ogoke, U. P., Riaz, M., Ibezim, E. N., Khan, J., Adedokun, K. A., Imodoye, S. O., Bello, I. O., & Awuchi, C. G. (2023). Wnt/β-catenin signaling pathway inhibitors, glycyrrhizic acid, solanine, polyphyllin I, crocin, hypericin, tubeimoside-1, diosmin, and rutin in medicinal plants have better binding affinities and anticancer properties: Molecular docking and ADMET study. Food Science & Nutrition, 11(7), 4155–4169.

Most read articles by the same author(s)