Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study

Necla Kulabaş; Tugce Yesil; İlkay Küçükgüzel

Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is characterized by a wide range of symptoms including fever, dry cough, headache, decreased sense of taste and smell, was first identified in Wuhan, China in December 2019. Currently, the nucleoside analog, remdesivir has been approved for emergency use authorization (EUA) by the regulatory agencies for the treatment of COVID-19 patients. The need for new antiviral agents has been continuing due to the some disadvantages of remdesivir. Molnupiravir (MLN) that is developed for the treatment of hepatitis C virus (HCV), have been reported to show antiviral activity against SARS-CoV-2 according to the results of a high throughput screen of nucleoside analogs and also phase II/III clinical trials of MLN is ongoing. In this study, fifty four MLN analogs (twelve of them are found to be reported in the literature whereas forty two of them are novel molecules) against SARS-CoV-2 RdRp were designed and evaluated for their potential antiviral activity by using molecular modelling studies. While among the designed MLN analogs, compound C17 was found to have the best potential inhibitor with -7.3 kcal/mol binding energy that is higher than molnupiravir and its active form EIDD-1931. Therefore, the isobutyric acid ester and monophosphate forms of C17 were also compared to the related MLN derivatives in terms of active site interactions. Lastly, the ten compounds with the best binding affinity including C17 were tested in silico for bioavailability, drug-likeness, ADME and safety profiles and were found to exhibit similar bioavailability and safety profile to MLN.

Keywords

References

[1] World Health Organization. Coronavirus disease (COVID-19) pandemic n.d. https://www.who.int/emergencies/diseases/novel-coronavirus-2019 (accessed October 2, 2021).
[2] Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 Variants of Concern in the United States—Challenges and Opportunities. JAMA. 2021; 325(11): 1037–1038.
[3] Parvez MSA, Karim MA, Hasan M, Jaman J, Karim Z, Tahsin T, Hasan MN, Hosen MJ. Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach. Int J Biol Macromol. 2020; 163: 1787–1797.
[4] Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci. 2020; 253: 117592.
[5] Tian L, Qiang T, Liang C, Ren X, Jia M, Zhang J, Li J, Wan M, YuWen X, Li H, Cao W, Liu H. RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic. Eur J Med Chem. 2021; 213: 113201.
[6] Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd, Liu H, Madden VJ, Krzystek HM, De C, White KK, Gully K, Schäfer A, Zaman T, Leist SR, Grant PO, Bluemling GR, Kolykhalov AA, Natchus MG, Askin FB, Painter G, Browne EP, Jones CD, Pickles RJ, Baric RS, Garcia JV. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021; 591(7850): 451–457.
[7] Zhou S, Hill CS, Sarkar S, Tse LV, Woodburn BMD, Schinazi RF, Sheahan TP, Baric RS, Heise MT, Swanstrom R. β- d-N4-hydroxycytidine Inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. J Infect Dis. 2021; 224(3): 415–419.
[8] Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, Höbartner C, Cramer P. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021; 28(9): 740–746.

[9] Rosenke K, Hansen F, Schwarz B, Feldmann F, Haddock E, Rosenke R, Barbian K, Meade-White K, Okumura A, Leventhal S, Hawman DW, Ricotta E, Bosio CM, Martens C, Saturday G, Feldmann H, Jarvis MA. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model. Nat Commun. 2021; 12(1): 2295.
[10] Menéndez-Arias L. Decoding molnupiravir-induced mutagenesis in SARS-CoV-2. J Biol Chem. 2021;297(1):100867.
[11] Bonnac LF, Mansky LM, Patterson SE. Structure-activity relationships and design of viral mutagens and application to lethal mutagenesis. J Med Chem. 2013; 56(23): 9403–9414. Research Article [12] Hollecker L, Choo H, Chong Y, Chu CK, Lostia S, McBrayer TR, Stuyver LJ, Mason JC, Du J, Rachakonda S, Shi J, Schinazi RF, Watanabe KA. Synthesis of β-enantiomers of N4-hydroxy-3′ -deoxypyrimidine nucleosides and their evaluation against bovine viral diarrhoea virus and hepatitis C virus in cell culture. Antivir Chem Chemother. 2004; 15(1): 43–55.
[13] Matthes E, Funk A, Krahn I, Gaertner K, von Janta-Lipinski M, Lin L, Will H, Sirma H. Strong and selective inhibitors of hepatitis B virus replication among novel N4-hydroxy- and 5-methyl-β-L-deoxycytidine analogues. Antimicrob Agents Chemother. 2007; 51(7): 2523–2530.
[14] Sun L, Peng Y, Yu W, Zhang Y, Liang L, Song C, Hou J, Qiao Y, Wang Q, Chen J, Wu M, Zhang D, Li E, Han Z, Zhao Q, Jin X, Zhang B, Huang Z, Chai J, Wang JH, Chang J. Mechanistic Insight into Antiretroviral Potency of 2′- Deoxy-2′-β-fluoro-4′-Azidocytidine (FNC) with a Long-Lasting Effect on HIV-1 Prevention. J Med Chem. 2020; 63(15): 8554–8566.
[15] Wang G, Smith DB, Beigelman L, Deval J, Prhavc M. Preparation of substituted nucleosides, nucleotides and analogs thereof as antiviral agents. US 20150051167 A1, 2015.
[16] Lili Y, Shaochun L. Substituted N4-hydroxycytidine derivatives and prodrug thereof for anti-novel coronavirus therapy. CN111548384A, 2020.
[17] Painter GR, Guthrie DB, Bluemling GR, Natchus MR. Preparation of N4-hydroxycytidine and derivatives and antiviral uses related thereto. WO 2017156380 A1, 2017.
[18] Esam Z, Akhavan M, lotfi M, Bekhradnia A. Molecular docking and dynamics studies of Nicotinamide Riboside as a potential multi-target nutraceutical against SARS-CoV-2 entry, replication, and transcription: A new insight. J Mol Struct. 2022; 1247: 131394.
[19] Raies AB, Bajic VB. In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci. 2016; 6(2): 147–172.
[20] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997; 23: 3–25.
[21] Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem. 2001; 44(12): 1841–1846.
[22] Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y. AdmetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model. 2012; 52(11): 3099–3105.
[23] Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015; 58(9): 4066–4072.
[24] Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7: 1–13.
[25] Sander T, Freyss J, Von Korff M, Rufener C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J Chem Inf Model. 2015; 55(2): 460–473.
[26] Lin JH, Yamazaki M. Role of P-Glycoprotein in Pharmacokinetics. Clin Pharmacokinet. 2003; 42(1): 59–98.
[27] Hubatsch I, Ragnarsson EGE, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007; 2(9): 2111–2119.
[28] van de Waterbeemd H, Gifford E. ADMET in silico modelling: Towards prediction paradise? Nat Rev Drug Discov. 2003; 2(3): 192–204.
[29] Miyagawa M. Globally harmonized system of classification and labelling of chemicals (GHS) and its implementation in Japan. Nihon Eiseigaku Zasshi. 2010; 65(1): 5-13.
[30] Toxicology Testing in the 21st Century (Tox21) n.d. https://www.epa.gov/chemical-research/toxicology-testing- 21st-century-tox21 (accessed October 6, 2021).
[31] Vitiello A, La Porta R, D’Aiuto V, Ferrara F. The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced. Egypt Liver J. 2021; 11: 11.
[32] Ivanyuk A, Livio F, Biollaz J, Buclin T. Renal Drug Transporters and Drug Interactions. Clin Pharmacokinet. 2017; 56(8): 825–892. Research Article [33] Ogu CC, Maxa JL. Drug Interactions Due to Cytochrome P450. Baylor Univ Med Cent Proc. 2000; 13: 421–423.
[34] Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021; 65(5): e02428-20.
[35] Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L, Ge J, Zheng L, Zhang Y, Wang H, Zhu Y, Zhu C, Hu T, Hua T, Zhang B, Yang X, Li J, Yang H, Liu Z, Xu W, Guddat LW, Wang Q, Lou Z, Rao Z. Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target 2020 (preprint).
[36] Stewart JJP. Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements. J Mol Model. 2007; 13(12): 1173–1213.
[37] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Software News and Updates Gabedit — A Graphical User Interface for Computational Chemistry Softwares. J Comput Chem. 2009; 30: 174–182.
[38] Oleg T, J. OA. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455–461.
[39] Ahmad J, Ikram S, Ahmad F, Rehman IU, Mushtaq M. SARS-CoV-2 RNA Dependent RNA polymerase (RdRp) – A drug repurposing study. Heliyon. 2020; 6(7): e04502.

Details

Primary Language

English

Subjects

Pharmaceutical Chemistry

Journal Section

Research Article

Authors

Necla Kulabaş ^*
Türkiye

Tugce Yesil
Türkiye

İlkay Küçükgüzel
Türkiye

Publication Date

June 28, 2025

Submission Date

October 9, 2021

Acceptance Date

November 1, 2021

Published in Issue

Year 2021 Volume: 25 Number: 6

IZ

https://izlik.org/JA97TW84CG

Cite

RIS / Bibtex

APA

Kulabaş, N., Yesil, T., & Küçükgüzel, İ. (2025). Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study. Journal of Research in Pharmacy, 25(6), 967-981. https://izlik.org/JA97TW84CG

AMA

1.Kulabaş N, Yesil T, Küçükgüzel İ. Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study. J. Res. Pharm. 2025;25(6):967-981. https://izlik.org/JA97TW84CG

Chicago

Kulabaş, Necla, Tugce Yesil, and İlkay Küçükgüzel. 2025. “Evaluation of Molnupiravir Analogues As Novel Coronavirus (SARS-CoV-2) RNA-Dependent RNA Polymerase (RdRp) Inhibitors – an in Silico Docking and ADMET Simulation Study”. Journal of Research in Pharmacy 25 (6): 967-81. https://izlik.org/JA97TW84CG.

EndNote

Kulabaş N, Yesil T, Küçükgüzel İ (July 1, 2025) Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study. Journal of Research in Pharmacy 25 6 967–981.

IEEE

[1]N. Kulabaş, T. Yesil, and İ. Küçükgüzel, “Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study”, J. Res. Pharm., vol. 25, no. 6, pp. 967–981, July 2025, [Online]. Available: https://izlik.org/JA97TW84CG

ISNAD

Kulabaş, Necla - Yesil, Tugce - Küçükgüzel, İlkay. “Evaluation of Molnupiravir Analogues As Novel Coronavirus (SARS-CoV-2) RNA-Dependent RNA Polymerase (RdRp) Inhibitors – an in Silico Docking and ADMET Simulation Study”. Journal of Research in Pharmacy 25/6 (July 1, 2025): 967-981. https://izlik.org/JA97TW84CG.

JAMA

1.Kulabaş N, Yesil T, Küçükgüzel İ. Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study. J. Res. Pharm. 2025;25:967–981.

MLA

Kulabaş, Necla, et al. “Evaluation of Molnupiravir Analogues As Novel Coronavirus (SARS-CoV-2) RNA-Dependent RNA Polymerase (RdRp) Inhibitors – an in Silico Docking and ADMET Simulation Study”. Journal of Research in Pharmacy, vol. 25, no. 6, July 2025, pp. 967-81, https://izlik.org/JA97TW84CG.

Vancouver

1.Necla Kulabaş, Tugce Yesil, İlkay Küçükgüzel. Evaluation of molnupiravir analogues as novel coronavirus (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) inhibitors – an in silico docking and ADMET simulation study. J. Res. Pharm. [Internet]. 2025 Jul. 1;25(6):967-81. Available from: https://izlik.org/JA97TW84CG