Structure-Based Virtual Screening of Antiviral Compounds Targeting the Norovirus RdRp Protein
Abstract
Background: Human noroviruses (NV) are the primary etiological organisms causing acute gastroenteritis around the world, causing severe morbidity and imposing a significant economic burden. The RNA-dependent RNA polymerase (RdRp) is essential for viral replication and could be a promising target for anti-NV therapeutics. Despite the discovery of a few NV RdRp inhibitors, the majority of these pharmaceuticals have demonstrated limited efficacy in inhibiting viral replication in cellular models.
Methods: In this study, computational screening of antiviral compounds was conducted targeting the NV RdRp protein. The assessment was based on binding poses and the key residues of RdRp involved in interactions with compounds.
Results: The compounds namely, Ribavirin, BMS806, Dihydromyricetin, R7935788, and LY2784544 were found to bind the RdRp protein with high affinity. Notably, these compounds displayed significantly lower binding affinities compared to the positive control, PPNDS. In addition, these compounds exhibited many RdRp protein binding residues that were also present in the PPNDS.
Conclusion: The results presented here suggest that these compounds have the potential to be used as inhibitors of NV RdRp in the development of antiviral medications. Nevertheless, due to the computational nature of this study, it is imperative to do experimental validation.
Keywords: Noroviruses; RdRp; Virtual screening; Antiviral Compounds
References
Koo HL, Ajami N, Atmar RL, DuPont HL. Noroviruses: The leading cause of gastroenteritis worldwide. Discovery Medicine, (2010); 10(50): 61-70.
Lopman BA, Steele D, Kirkwood CD, Parashar UD. The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control. PLOS Medicine, (2016); 13(4): e1001999.
Hall AJ. Noroviruses: the perfect human pathogens? The Journal of Infectious Diseases, (2012); 205(11): 1622-1624.
Kaufman SS, Green KY, Korba BE. Treatment of norovirus infections: moving antivirals from the bench to the bedside. Antiviral Research, (2014); 105: 80-91.
Rocha-Pereira J, Neyts J, Jochmans D. Norovirus: targets and tools in antiviral drug discovery. Biochemical Pharmacology, (2014); 91(1): 1-11.
Ebenezer O, Jordaan MA, Damoyi N, Shapi M. Discovery of Potential Inhibitors for RNA-Dependent RNA Polymerase of Norovirus: Virtual Screening, and Molecular Dynamics. International Journal of Molecular Sciences, (2020); 22(1): 171.
Yates MK, Seley-Radtke KL. The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Research, (2019); 162: 5-21.
Mastrangelo E, Pezzullo M, Tarantino D, Petazzi R, Germani F, et al. Structure-based inhibition of Norovirus RNA-dependent RNA polymerases. Journal of Molecular Biology, (2012); 419(3-4): 198-210.
S MAK, Hosen MA, Ahmad S, El Bakri Y, Laaroussi H, et al. Potential SARS-CoV-2 RdRp inhibitors of cytidine derivatives: Molecular docking, molecular dynamic simulations, ADMET, and POM analyses for the identification of pharmacophore sites. PLoS One, (2022); 17(11): e0273256.
Bassetto M, Van Dycke J, Neyts J, Brancale A, Rocha-Pereira J. Targeting the Viral Polymerase of Diarrhea-Causing Viruses as a Strategy to Develop a Single Broad-Spectrum Antiviral Therapy. Viruses, (2019); 11(2): 173.
Tarantino D, Pezzullo M, Mastrangelo E, Croci R, Rohayem J, et al. Naphthalene-sulfonate inhibitors of human norovirus RNA-dependent RNA-polymerase. Antiviral Research, (2014); 102: 23-28.
Kireev D. Structure-Based Virtual Screening of Commercially Available Compound Libraries. Methods in Molecular Biology, (2016); 1439: 65-76.
Kontoyianni M. Docking and Virtual Screening in Drug Discovery. Methods in Molecular Biology, (2017); 1647: 255-266.
Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods in Molecular Biology, (2015); 1263: 243-250.
Sait KHW, Mashraqi M, Khogeer AA, Alzahrani O, Anfinan NM, et al. Molecular docking analysis of HER-2 inhibitor from the ZINC database as anticancer agents. Bioinformation, (2020); 16(11): 882-887.
Sait KHW, Alam Q, Anfinan N, Al-Ghamdi O, Malik A, et al. Structure-based virtual screening and molecular docking for the identification of potential novel EGFRkinase inhibitors against ovarian cancer. Bioinformation, (2019); 15(4): 287-294.
Sayed Murad HA, M MR, Alqahtani SM, B SR, Alghamdi S, et al. Molecular docking analysis of AGTR1 antagonists. Bioinformation, (2023); 19(3): 284-289.
I JH, Alsharif FH, Aljadani M, Fahad Alabbas I, Faqihi MS, et al. Molecular docking analysis of KRAS inhibitors for cancer management. Bioinformation, (2023); 19(4): 411-416.
Baluom M, Grossbard EB, Mant T, Lau DT. Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. British Journal of Clinical Pharmacology, (2013); 76(1): 78-88.
Lin PF, Blair W, Wang T, Spicer T, Guo Q, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proceedings of the National Academy of Sciences of the United States of America, (2003); 100(19): 11013-11018.
Liu D, Mao Y, Ding L, Zeng XA. Dihydromyricetin: A review on identification and quantification methods, biological activities, chemical stability, metabolism and approaches to enhance its bioavailability. Trends in Food Science & Technology, (2019); 91: 586-597.
Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer Journal, (2013); 3(4): e109.
Beaucourt S, Vignuzzi M. Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance. Current Opinion in Virology, (2014); 8: 10-15.
DOI: http://dx.doi.org/10.62940/als.v11i2.2830
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