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ORIGINAL RESEARCH

Pharmacophore modeling and molecular docking analysis of glycyrrhizin as a potential anti-COVID-19 agent

Leyla Galandarli1 ,  Gulnara Akverdieva2 ,  Nurlan Amrahov3 ,  Rovshan Khalilov4 ,  Afsun Sujayev5*
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1 Department of “Young Talents” Lyceum, Baku State University, Baku, Azerbaijan
2 Biophysics Division of Institute for Physical Problems, Baku State University, Baku, Azerbaijan
3 Bioengineering SRL, The Center of Excellence in Research, Development, and Innovation, Baku State University, Baku, Azerbaijan
4 Department of Biophysics and Biochemistry, Faculty of Biology, Baku State University, Baku, Azerbaijan
5 Laboratory of Physiologically Active Organic Compounds of Institute of Chemistry of Additives National Academy of Sciences, Baku, Azerbaijan
BMT, 117 https://doi.org/10.12336/bmt.25.00117
Submitted: 27 July 2025 | Revised: 10 October 2025 | Accepted: 5 November 2025 | Published: 26 November 2025
© 2025 by the Author(s). Licensee Biomaterials Translational, USA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 (CC BY-NC-SA 4.0) (https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en)
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Abstract

Traditional herbal medicines are widely used as complementary treatments for viral infections. Glycyrrhizin (GLR), a compound found in licorice root, has been proposed as a potential therapeutic agent for COVID-19. This study investigates the molecular interactions between GLR and two key severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins—the main protease (Mpro) and the spike glycoprotein—using molecular docking simulations. Docking analyses were performed using AutoDock Vina, targeting SARS-CoV-2 Mpro (Protein Data Bank ID: 7ZQV) and the spike glycoprotein (Protein Data Bank ID: 6VXX). A site-specific docking approach was applied for all calculations. The binding sites were defined based on crystallized ligand-bound complexes, and a grid box of 40 × 40 × 40 points was applied for both receptors. The target proteins were kept rigid, while the ligand was allowed to remain flexible during both simulation procedures. The optimal conformation of the ligand was selected by ranking the binding energies of its poses according to the complex intermolecular interactions. PyMOL and Discovery Studio 3.1 were employed for visualization and interaction analysis. Results showed that GLR binds at the active site of the receptors, forming key interactions. The docking scores indicated strong binding affinities of −8.8 kcal/mol for the 7ZQV target and −9.5 kcal/mol for the 6VXX target, suggesting that GLR may serve as a potential inhibitor of these targets. Drawing on the derived computational findings, models of a pharmacophore for GLR binding to the specified receptors were proposed. These findings provide valuable insights into the molecular basis of GLR’s antiviral activity and may guide the design of novel anti-COVID-19 therapeutics derived from natural compounds.

Keywords
Glycyrrhizin
Severe acute respiratory syndrome coronavirus 2 main protease
Severe acute respiratory syndrome coronavirus 2 spike glycoprotein
Molecular docking
Pharmacophore model
COVID-19
Funding
None.
Conflict of interest
The authors declare no conflicts of interest.
References
  1. Demir Y. Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases. Drug Dev Res. 2020;81(6):628-636. doi: 10.1002/ddr.21667

 

  1. Demir Y. Exploring the inhibitory effects of quinolone medications on carbonic anhydrase enzyme activity: In vitro and in silico investigation. Chem Select. 2024;9(30):2365-6549. doi: 10.1002/slct.202402129

 

  1. Özdemir K, Demir Y. Phenolic compounds in exercise physiology: Dual role in oxidative stress and recovery adaptation. Food Sci Nutr. 2025;13(8):e70714. doi: 10.1002/fsn3.70714

 

  1. Ji X, Liu N, Huang S, Zhang C. A comprehensive review of licorice: The preparation, chemical composition, bioactivities and its applications. Am J Chin Med. 2024;52(3):667-716. doi: 10.1142/S0192415X24500289

 

  1. Wu Y, Wang Z, Du Q, et al. Pharmacological effects and underlying mechanisms of licorice-derived flavonoids. Evid Based Complement Alternat Med. 2022;2022:9523071. doi: 10.1155/2022/9523071

 

  1. Ploeger B, Mensinga T, Sips A, Seinen W, Meulenbelt J, DeJongh J. The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling. Drug Metab Rev. 2001;33(2):125-147. doi: 10.1081/DMR-100104400

 

  1. Moustafa GO, Shalaby A, Naglah AM, Mounier MM, Anwar MM, Nossier ESS. Synthesis, characterization, in vitro anticancer potentiality, and antimicrobial activities of novel peptide-glycyrrhetinic-acid-based derivatives. Molecules. 2020;26(15):4573. doi: 10.3390/molecules26154573

 

  1. Fujii S, Tuvshintogtokh I, Mandakh B, et al. Screening of Glycyrrhiza uralensis Fisch. ex DC. Containing high concentrations of glycyrrhizin by Eastern blotting and enzyme-linked immunosorbent assay using anti-glycyrrhizin monoclonal antibody for selective breeding of licorice. J Nat Med. 2014;68(4):717-722. doi: 10.1007/s11418-014-0847-7

 

  1. Ming LJ, Yin AC. Therapeutic effects of glycyrrhizic acid. Nat Prod Commun. 2013;8(3):415-418.

 

  1. Shajini BY, Krishnan D, Dev BS, et al. Potential benefits of Glycyrrhiza glabra (Liquorice) herb, its chemical make-up and significance in safeguarding poultry health: Current scientific knowledge. J Exp Biol Agric Sci. 2023;11(3):462-478. doi: 10.18006/2023.11(3).462.478

 

  1. Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm Biol. 2017;55(1):5-18. doi: 10.1080/13880209

 

  1. Shah SL, Wahid F, Khan N, et al. Inhibitory effects of Glycyrrhiza glabra and its major constituent glycyrrhizin on inflammation-associated corneal neovascularization. Evid Based Complement Alternat Med. 2018;2018:8438101. doi: 10.1155/2018/8438101

 

  1. Shiba F, Miyauchi M, Chea C, et al. Anti-inflammatory effect of glycyrrhizin with Equisetum arvense extract. Odontology. 2021;109(2):464-473. doi:10.1007/s10266-020-00563-3

 

  1. Leite CDS, Bonafé GA, Carvalho Santos J, Martinez CAR, Ortega MM, Ribeiro ML. The anti-inflammatory properties of licorice (Glycyrrhiza glabra)-derived compounds in intestinal disorders. Int J Molecular Sci. 2022;23(8):4121. doi: 10.3390/ijms23084121

 

  1. Li C, Li L, Lan T. Co-treatment with disulfiram and glycyrrhizic acid suppresses the inflammatory response of chondrocytes. J Orthop Surg Res. 2021;16(1):132. doi: 10.1186/s13018-021-02262-3

 

  1. Ashfaq UA, Masoud MS, Nawaz Z. Glycyrrhizin as an antiviral agent against hepatitis C virus. J Transl Med. 2011;9(1):112. doi: 10.1186/1479-5876-9-112

 

  1. Nada F, Abo El-Magd A, Amro El-Karef M, El-Shishtawy MM, Eissa LA. Hepatoprotective effects of glycyrrhizin and omega-3 fatty acids on nuclear factor-kappa B pathway in thioacetamide-induced fibrosis in rats. Egypt J Basic Appl Sci. 2015;2(2):65-74. doi: 10.1016/j.ejbas.2014.12.005

 

  1. Li JY, Cao HY, Liu P, Cheng GH, Sun MY. Glycyrrhizic acid in the treatment of liver diseases: Literature review. Biomed Res Int. 2014;2014:872139. doi: 10.1155/2014/872139

 

  1. Xu F, Huang X, Wu H, Wang X. Screening compounds for treating the diabetes and COVID-19 from Miao medicine by molecular docking and bioinformatics. Arab J Chem. 2023;16(9):105001. doi: 10.1016/j.arabjc.2023.105001

 

  1. Baltina LA, Tasi YT, Huang SH, et al. Glycyrrhizic acid derivatives as dengue virus inhibitors. Bioorg Med Chem Lett. 2019;29(20):126645. doi: 10.1016/j.bmcl.2019.126645

 

  1. Wolkerstorfer A, Kurz H, Bachhofner N, Szolar OH. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res. 2009;83(2):171-178. doi: 10.1016/j.antiviral.2009.04.012

 

  1. Han S, Sun L, He F, Che H. Anti-allergic activity of glycyrrhizic acid on IgE-mediated allergic reaction by regulation of allergy-related immune cells. Sci Rep. 2017;7(1):7222. doi: 10.1038/s41598-017-07833-1

 

  1. Sharma R, Santosh K, Guru S, et al. 3-(2,6-Dichloro-benzyloxy)-11-oxo-olean-12-ene-29-oic acid, a semisynthetic derivative of glycyrrhetic acid: Synthesis, antiproliferative, apoptotic, and anti-angiogenesis activity. Med Chem Commun. 2015;6:564. doi: 10.1039/b000000x

 

  1. Ahmad A, Tiwari RK, Mishra P, et al. Antiproliferative and apoptotic potential of glycyrrhizin against HPV16+ Caski cervical cancer cells: A plausible association with downregulation of HPV E6 and E7 oncogenes and Notch signaling pathway. Saudi J Biol Sci. 2022;29(5):3264-3275. doi: 10.1016/j.sjbs.2022.01.054

 

  1. Cheng X, Liu Y, Qi B, et al. Glycyrrhizic acid alleviated MI/R-induced injuries by inhibiting Hippo/YAP signaling pathways. Cell Signal. 2024;115:111036. doi: 10.1016/j.cellsig.2024.111036

 

  1. Yamamoto M, Nagasawa Y, Fujimori K. Glycyrrhizic acid suppresses the early stage of adipogenesis through repression of MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells. Chem Biol Interact. 2021;346:109595. doi: 10.1016/j.cbi.2021.109595

 

  1. Lv X, Zhu Y, Deng Y, et al. Glycyrrhizin improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway to prevent doxorubicin-induced cardiotoxicity. Toxicology. 2020;441:152508. doi: 10.1016/j.tox.2020.152508

 

  1. Van De Sand L, Bormann M, Alt M, et al. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses. 2021;13(4):609. doi: 10.3390/v13040609

 

  1. Maddah M, Bahramsoltani R, Hoseini YN, Rahimi R, Aliabadi R, Pourfath M. Proposing high-affinity inhibitors from Glycyrrhiza glabra L. Against SARS-CoV-2 infection: Virtual screening and computational analysis. New J Chem. 2021;45:15977-15995. doi: 10.1039/D1NJ02031E

 

  1. Banerjee S, Baidya SK, Adhikari N, Ghosh B, Jha T. Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences. J Mol Struct. 2023;1275:134642. doi: 10.1016/j.molstruc.2022.134642

 

  1. Gomaa AA, Abdel-Wadood YA, Gomaa MA. Glycyrrhizin and boswellic acids, the golden nutraceuticals: Multitargeting for treatment of mild-moderate COVID-19 and prevention of post-COVID cognitive impairment. Inflammopharmacol. 2022;30(6):1977-1992. doi: 10.1007/s10787-022-01062-3

 

  1. Bijelić K, Hitl M, Kladar N. Phytochemicals in the prevention and treatment of SARS-CoV-2-clinical evidence. Antibiotics (Basel). 2022;11(11):1614. doi: 10.3390/antibiotics11111614

 

  1. Zhang B, Qi F. Herbal medicines exhibit a high affinity for ACE2 in treating COVID-19. Biosci Trends. 2023;17(1):14-20. doi: 10.5582/bst.2022.01534

 

  1. He MF, Liang JH, Shen YN, et al. Glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2. Life (Basel). 2022;12(11):1706. doi: 10.3390/life12111706

 

  1. Antonopoulou I, Sapountzaki E, Rova U, Christakopoulos P. Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds. Comput Struct Biotechnol J. 2022;20:1306-1344. doi: 10.1016/j.csbj.2022.03.009

 

  1. Lei R, Qing E, Odle A, et al. Functional and Antigenic Characterization of SARS-CoV-2 Spike Fusion Peptide by Deep Mutational Scanning. bioRxiv [Preprint]; 2023. doi: 10.1101/2023.11.28.569051

 

  1. Garrett ME, Galloway JG, Wolf C, et al. Comprehensive characterization of the antibody responses to SARS-CoV-2 spike protein finds additional vaccine-induced epitopes beyond those for mild infection. Elife. 2022;11:e73490. doi: 10.7554/eLife.73490

 

  1. Laporte M, Raeymaekers V, Van Berwaer R, et al. The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways. PLoS Pathog. 2021;17(4):e1009500. doi: 10.1371/journal.ppat.1009500

 

  1. Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today. 2020;25(4):668-688. doi: 10.1016/j.drudis.2020.01.015

 

  1. Johnson MC, Lyddon TD, Suarez R, et al. Optimized pseudotyping conditions for the SARS-COV-2 spike glycoprotein. J Virol. 2020;94(21):e01062-20. doi: 10.1128/JVI.01062-20

 

  1. Takeda M. Proteolytic activation of SARS-CoV-2 spike protein. Microbiol Immunol. 2021;66(1):15-23. doi: 10.1111/1348-0421.12945

 

  1. Karağaç MS, Yeşilkent EN, Kizir D, et al. Esculetin improves inflammation of the kidney via gene expression against doxorubicin-induced nephrotoxicity in rats: In vivo and in silico studies. Food Biosci. 2024;62:105159. doi: 10.1016/j.fbio.2024.105159

 

  1. Demir Y, Öztürk N, Isıyel M, Ceylan H. Effects of carnosic and usnic acid on pentose phosphate pathway enzymes: An experimental and molecular docking study. Chem Select. 2024;9(27):e202401067. doi: 10.1002/slct.202401067

 

  1. Sever B, Altıntop MD, Demir Y, et al. Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines. Chem Biol Interact. 2021;345:109576. doi: 10.1016/j.cbi.2021.109576

 

  1. Tahirli S, Aliyeva F, Şenol H, et al. Novel complex compounds of nickel with 3-(1-phenyl-2,3-dimethyl-pyrazolone-5)azopentadione-2,4: Synthesis, NBO analysis, reactivity descriptors and in silico and in vitro anti-cancer and bioactivity studies. J Biomol Struct Dyn. 2024;43:5552-5576. doi: 10.1080/07391102.2024.2309646

 

  1. Galandarli L, Akverdieva G. Molecular docking evaluation of glycyrrhizin as anti-stress and anti-diabetic agent. New Mater Compd Appl. 2025;9(2):223-239. doi: 10.62476/nmca.92223

 

  1. Trott O, Olson AJ. 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. doi: 10.1002/jcc.21334

 

  1. Yonekura-Sakakibara K, Saito K. Functional genomics for plant natural product biosynthesis. Nat Prod Rep. 2009;26:1466-1487. doi: 10.1039/B817077K

 

  1. Fàbrega-Ferrer M, Herrera-Morandé A, Muriel-Goñi S, et al. Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404. Antiviral Res. 2022;208:105458. doi: 10.1016/j.antiviral.2022.105458

 

  1. Walls AC, Park Y, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181(2):281-292.e6. doi: 10.1016/j.cell.2020.02.058

 

  1. DeLano WL. The PyMOL Molecular Graphics System; 2010. Available from: https://www.ccp4.ac.uk/newsletters/newsletter40/11_pymol.pdf [Last accessed on 2025 Oct 30].

 

  1. Discovery Studio 3.1. Discovery Studio Visualization. Available from: https://accelrys.com/products/collaborative/science/biovia/discovery/ studio/visualization-download.php [Last accessed on 2016 Dec 02].

 

  1. Liu X, Wang XJ. Potential inhibitors against the 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics. 2020;47(2):119-121. doi: 10.1016/j.jgg.2020.02.001

 

  1. Chaurasiya A, Shome A, Chawla PA. Molecular docking analysis of peptide-based antiviral agents against SARS-CoV-2 main protease: An approach towards drug repurposing. Explor Med. 2023;4:33-44. doi: 10.37349/emed.2023.00123

 

  1. Yılmaz G, Çelik S, Erbölükbaş Özel A, Akyüz S. In silico evaluation of ERQ bioactive tripeptide as an anticancer agent and an inhibitor of SARS-CoV-2 enzymes. Eur J Biol. 2024;83:34-41. doi: 10.26650/EurJBiol.2024.1389569

 

  1. Begum SKA, Begum S, Bandari P, Swapna BS, Reddemma MT. Tetrandrine, an effective inhibitor of COVID-19 main protease (Mpro); Insights from molecular docking and dynamics simulations. Int J Pharm Investig. 2023;13(4):845-851. doi: 10.5530/ijpi.13.4.106

 

  1. Çelik S, Yılmaz G, Akyüz S, Özel AE. Shedding light on the biological activity of aminopterin, via molecular structural, docking, and molecular dynamics analyses. J Biomol Struct Dyn. 2023;1-22. doi: 10.1080/07391102.2023.2245493

 

  1. Hatada R, Okuwaki K, Mochizuki Y. Fragment molecular orbital-based interaction analyses on COVID-19 main protease - inhibitor N3 complex (PDB ID: 6LU7). J Chem Inf Model. 2020;60(7):3593-3602. doi: 10.1021/acs.jcim.0c00283

 

  1. Sagaama A, Brandan SA, Ben Issa T, Issaoui N. Searching potential antiviral candidates for the treatment of the 2019 novel coronavirus based on DFT calculations and molecular docking. Heliyon. 2020;6(8):e04640. doi: 10.1016/j.heliyon.2020.e04640

 

  1. Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential Inhibitor of COVID-19 Main Protease (Mpro) from Several Medicinal Plant Compounds by Molecular Docking Study. [Preprint]; 2020. doi: 10.20944/preprints202003.0226.v1

 

  1. Rai H, Barik A, Singh YP, et al. Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: An effort toward drug repurposing to combat COVID-19. Mol Divers. 2021;25:1905-1927. doi: 10.1007/s11030-021-10188-5

 

  1. Srivastava V, Yadav A, Sarkar P. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc. 2022;49(8):2999-3007. doi: 10.1016/j.matpr.2020.10.055

 

  1. Çelik S, Akyüz S, Özel AE. Vibrational spectroscopic characterization and structural investigations of Cepharanthine, a natural alkaloid. J Mol Struct. 2022;1258:132693. doi: 10.1016/j.molstruc.2022.132693

 

  1. Joshi A, Sharma V, Singh J, Kaushik V. Chemi-informatic approach to investigate putative pharmacoactive agents of plant origin to eradicate COVID-19. Coronaviruses. 2020;3(3):40-54. doi: 10.2174/2666796701999201203210036

 

  1. Holanda VN, Lima EMA, Silva WVD, et al. Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: A virtual screening, docking, and molecular dynamics study. J Biomol Struct Dyn. 2022;40(12):5462-5480. doi: 10.1080/07391102.2020.1871073

 

  1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA. 2020;323(18):1824-1836. doi: 10.1001/jama.2020.6019

 

  1. Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies. J Ethnopharmacol. 2018;225:342-358. doi: 10.1016/j.jep.2018.05.019
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