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Review
. 2023 Mar 5:1275:134642.
doi: 10.1016/j.molstruc.2022.134642. Epub 2022 Nov 25.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences

Suvankar Banerjee  1 , Sandip Kumar Baidya  1 , Nilanjan Adhikari  1 , Balaram Ghosh  2 , Tarun Jha  1
Affiliations
Review

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences

Suvankar Banerjee et al. J Mol Struct. .

Abstract

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Keywords: 11β-HSD, 11β-hydroxysteroid dehydrogenase; 3CLpro, 3-chymotrypsin-like protease; ACE2, Angiotensin converting enzyme 2; ADMET, absorption distribution metabolism excretion and toxicity; ARDS, acute respiratory distress syndrome; CHM, Chinese herbal medicine; CNS, central nervous system; COVID-19, Coronavirus Disease 2019; CTD, C-terminal domain; Experimental and computational evidences; Glycyrrhizin; HMGB1, high-mobility-group box1; IL, Interleukin; INF-γ, interferon-γ; KEGG, Kyoto Encyclopedia of Genes and Genomes; MD, molecular dynamics; MERS, Middle East respiratory syndrome; MM/GBSA, Molecular Mechanics/Generalized Born Surface Area; MM/PBSA, Molecular Mechanics Poisson-Boltzmann Surface Area; MR, mineralocorticoid receptor; Molecular docking interactions; NO, nitric oxide; NTD, N-terminal domain; ORF, open reading frame; PLpro, papain-like protease; RBD, receptor-binding domain; RMSD, Root mean square deviation; RMSF, Root mean square fluctuation; ROS, reactive oxygen species; RSV, respiratory syncytial virus; RTC, replication-transcription complex; RdRp, RNA-dependent RNA polymerase; SARS-CoV-2; SARS-CoV-2, Severe acute respiratory syndrome coronavirus-2; SI, Selectivity index; TCM, Traditional Chinese Medicine; TLR, Toll-like receptor; TNF-α, Tumor necrosis factor α; Traditional Chinese medicine; nsp, non-structural protein.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Image, graphical abstract
Graphical abstract
Fig 1
Fig. 1
The potential effect of compounds of Glycyrrhiza species against diverse disease conditions.
Fig 2
Fig. 2
Structural morphology of coronavirus.
Fig 3
Fig. 3
Replication cycle of SARS-CoV-2.
Fig 4
Fig. 4
Compounds obtained from Glycyrrhiza species (A) Triterpenoid derivatives (B) Flavones, chalcones, and coumarins.
Fig 5
Fig. 5
Synthesized glycyrrhizin derivatives and their activity against SARS-CoV.
Fig 6
Fig. 6
Summary of the possible mode of action of glycyrrhizin against SARS-CoV-2 infection.
Fig 7
Fig. 7
Glycyrrhizin bound to the active site of SARS-CoV-2 Mpro (PDB: 6LU7). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 8
Fig. 8
Glycyrrhizin bound to the active site of SARS-CoV-2 3CLpro (PDB: 6Y2F). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 9
Fig. 9
Glycyrrhizin bound to the active site of SARS-CoV-2 3CLpro (PDB: 6Y2E). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 10
Fig. 10
Binding mode of interaction of glycyrrhizin with SARS-CoV-2 (A) RdRp (PDB: 6M71) (B) ACE2 (PDB: 6M17). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 11
Fig. 11
Binding mode of interaction of glycyrrhizin with ACE2 enzyme of SARS-CoV-2 (PDB: 6LZG). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 12
Fig. 12
Binding mode of interaction of glycyrrhizin with ACE2 binding site of the RBD of SARS-CoV-2 spike protein (PDB: 6ACD). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 13
Fig. 13
Binding mode of interaction of glycyrrhizin with SARS-CoV-2 (A) RBD bound with ACE2 (PDB: 6LZG) (B) 3CLpro (PDB: 7BQY) (C) PLpro (PDB: 6XAA) and (D) Nucleocapsid (N) protein (PDB: 6M3M). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 14
Fig. 14
Binding interaction of glycyrrhizin with SARS-CoV-2 RBD domain complexed with ACE2. [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 15
Fig. 15
Binding interaction of (A) Glycyrrhizin (B) Liquiritin (C) Glyasperin A and (D) Isoliquiritin apioside with SARS-CoV-2 spike glycoprotein (PDB: 6VSB). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 16
Fig. 16
Binding interaction of (A) Glycyrrhizin (B) Dihydroglyasperin C (C) Liquiritin (D) Glyasperin A (E) Isoliquiritin apioside and (F) Licochalcone D with SARS-CoV-2 nsp15 endoribonuclease (PDB: 6W01). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 17
Fig. 17
Binding mode of interaction of glycyrrhizin with SARS-CoV-2 nsp15 endoribonuclease (PDB: 6OW1). [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 18
Fig. 18
Binding interaction of glycyrrhizin with SARS-CoV-2 nsp1 protein. [Hydrogen bonding interactions are depicted in dotted green arrow].
Fig 19
Fig. 19
Glycyrrhizin and related derivatives simultaneously block targets of SARS-CoV-2 life cycle.
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