Discovery of Ganoderma Lucidum Triterpenoids As Potential Inhibitors Against Dengue Virus NS2B-NS3 Protease

Overview

Journal Sci Rep

Specialty Science

Date 2019 Dec 15

PMID 31836806

Citations 39

Authors

Shiv Bharadwaj

Kyung Eun Lee

Vivek Dhar Dwivedi

Umesh Yadava

Aleksha Panwar

Stuart J Lucas

Amit Pandey

Sang Gu Kang

Affiliations

Soon will be listed here.

Abstract

Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacologically bioactive compounds and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in vitro assay. From in silico analysis of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz. Ganodermanontriol (-6.291 kcal/mol), Lucidumol A (-5.993 kcal/mol), Ganoderic acid C2 (-5.948 kcal/mol) and Ganosporeric acid A (-5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to reference inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (-5.377 kcal/mol). These results were further studied for binding affinity and stability using the molecular mechanics/generalized Born surface area method and Molecular Dynamics simulations, respectively. Also, in vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.

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References

Kim S, Thiessen P, Bolton E, Chen J, Fu G, Gindulyte A . PubChem Substance and Compound databases. Nucleic Acids Res. 2015; 44(D1):D1202-13. PMC: 4702940. DOI: 10.1093/nar/gkv951. View

Newman D, Cragg G . Natural Products as Sources of New Drugs from 1981 to 2014. J Nat Prod. 2016; 79(3):629-61. DOI: 10.1021/acs.jnatprod.5b01055. View

Eo S, Kim Y, Lee C, Han S . Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum. J Ethnopharmacol. 2000; 68(1-3):129-36. DOI: 10.1016/s0378-8741(99)00067-7. View

Friesner R, Murphy R, Repasky M, Frye L, Greenwood J, Halgren T . Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49(21):6177-96. DOI: 10.1021/jm051256o. View

Le Duyen H, Cerny D, Trung D, Pang J, Velumani S, Toh Y . Skin dendritic cell and T cell activation associated with dengue shock syndrome. Sci Rep. 2017; 7(1):14224. PMC: 5660158. DOI: 10.1038/s41598-017-14640-1. View

Meselhy M, Nakamura N, Tezuka Y, Hattori M, Kakiuchi N, Shimotohno K . Anti-HIV-1 and anti-HIV-1-protease substances from Ganoderma lucidum. Phytochemistry. 1998; 49(6):1651-7. DOI: 10.1016/s0031-9422(98)00254-4. View

Martins V, Alencar C, Kamimura M, Kamimura M, de Carvalho Araujo F, Simone S . Occurrence of natural vertical transmission of dengue-2 and dengue-3 viruses in Aedes aegypti and Aedes albopictus in Fortaleza, Ceará, Brazil. PLoS One. 2012; 7(7):e41386. PMC: 3405123. DOI: 10.1371/journal.pone.0041386. View

Zhu Q, Bang T, Ohnuki K, Sawai T, Sawai K, Shimizu K . Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015; 5:13194. PMC: 4549708. DOI: 10.1038/srep13194. View

Matuszewska A, Jaszek M, Stefaniuk D, Ciszewski T, Matuszewski L . Anticancer, antioxidant, and antibacterial activities of low molecular weight bioactive subfractions isolated from cultures of wood degrading fungus Cerrena unicolor. PLoS One. 2018; 13(6):e0197044. PMC: 5991343. DOI: 10.1371/journal.pone.0197044. View

10.

Sanodiya B, Thakur G, Baghel R, Prasad G, Bisen P . Ganoderma lucidum: a potent pharmacological macrofungus. Curr Pharm Biotechnol. 2009; 10(8):717-42. DOI: 10.2174/138920109789978757. View

11.

Matusan A, Pryor M, Davidson A, Wright P . Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: effects on enzyme activity and virus replication. J Virol. 2001; 75(20):9633-43. PMC: 114534. DOI: 10.1128/JVI.75.20.9633-9643.2001. View

12.

Taguchi Y . Principal Components Analysis Based Unsupervised Feature Extraction Applied to Gene Expression Analysis of Blood from Dengue Haemorrhagic Fever Patients. Sci Rep. 2017; 7:44016. PMC: 5343617. DOI: 10.1038/srep44016. View

13.

Gibbs A, Steele R, Liu G, Tounge B, Montelione G . Inhibitor Bound Dengue NS2B-NS3pro Reveals Multiple Dynamic Binding Modes. Biochemistry. 2018; 57(10):1591-1602. DOI: 10.1021/acs.biochem.7b01127. View

14.

Over B, Wetzel S, Grutter C, Nakai Y, Renner S, Rauh D . Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem. 2012; 5(1):21-8. DOI: 10.1038/nchem.1506. View

15.

Chang C, Lin C, Lu C, Martel J, Ko Y, Ojcius D . Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Nat Commun. 2015; 6:7489. PMC: 4557287. DOI: 10.1038/ncomms8489. View

16.

Oliveira M, Lert-Itthiporn W, Cavadas B, Fernandes V, Chuansumrit A, Anunciacao O . Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome. PLoS Negl Trop Dis. 2018; 12(2):e0006202. PMC: 5813895. DOI: 10.1371/journal.pntd.0006202. View

17.

Guo Z, Mohanty U, Noehre J, Sawyer T, Sherman W, Krilov G . Probing the alpha-helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis. Chem Biol Drug Des. 2010; 75(4):348-59. DOI: 10.1111/j.1747-0285.2010.00951.x. View

18.

Ma B, Ren W, Zhou Y, Ma J, Ruan Y, Wen C . Triterpenoids from the spores of Ganoderma lucidum. N Am J Med Sci. 2012; 3(11):495-8. PMC: 3271404. DOI: 10.4297/najms.2011.3495. View

19.

Chen W, Luo S, Ll H, Yang H . [Effects of ganoderma lucidum polysaccharides on serum lipids and lipoperoxidation in experimental hyperlipidemic rats]. Zhongguo Zhong Yao Za Zhi. 2005; 30(17):1358-60. View

20.

Medigeshi G, Kumar R, Dhamija E, Agrawal T, Kar M . N-Desmethylclozapine, Fluoxetine, and Salmeterol Inhibit Postentry Stages of the Dengue Virus Life Cycle. Antimicrob Agents Chemother. 2016; 60(11):6709-6718. PMC: 5075077. DOI: 10.1128/AAC.01367-16. View