Generic placeholder image

Current Nutrition & Food Science


ISSN (Print): 1573-4013
ISSN (Online): 2212-3881

Research Article

In Silico Study of the Active Compounds of Lindera aggregata (Sims) Kosterm as Anti-coronavirus

Author(s): Elok R. Firdiana*, Elga Renjana, Linda W. Ningrum, Melisnawati H. Angio, Muhamad Nikmatullah and Syaiful Rizal

Volume 17, Issue 4, 2021

Published on: 01 September, 2020

Page: [408 - 416] Pages: 9

DOI: 10.2174/1573401316999200901181217


Background: CoVID-19, caused by a new type of coronavirus named SARS-CoV-2, has become a pandemic. Together with SARS-CoV and MERS-CoV, CoVID-19 is a large global outbreak of coronavirus infection; however, its rate of spread is much higher. Since the vaccines and anti-SARS-CoV-2 have not been found, a faster control mechanism is much needed. Traditional herbs have shown the potential for this purpose, as has been demonstrated by the Chinese Government with a high success rate. One of the herbs used was Lindera aggregata, which is part of the collection in Purwodadi Botanic Gardens.

Objectives: Through in silico study, this research aims to reveal the secondary metabolites contained in L. aggregata that have the potential to serve as anti-SARS-CoV-2 medication as well as showcase their inhibitory mechanisms.

Methods: The research was conducted through molecular docking analysis of terpenoids and alkaloids contained in the root of L. aggregata, with target proteins 3CLpro, PLpro, Spike, and ACE 2 playing a role in SARS-CoV-2 infection.

Result: All analyzed compounds tended to interact with all four target proteins with different binding affinity values, but the interaction seemed stronger with 3CLpro and Spike. Terpenoids, linderane and linderalactone had the strongest interaction tendency with 3CLpro, PLpro, and Spike; the compound norboldine, an alkaloid, had the strongest interaction with ACE 2, with a binding affinity value of -8.2 kcal/mol.

Conclusion: Terpenoids and alkaloids contained in the root of L. aggregata, which caused inhibition of adsorption and replication of SARS-CoV-2, could serve as anti-SARS-CoV-2.

Keywords: Active compound, anti-coronavirus, CoVID-19, in silico, Lindera aggregata, molecular docking.

Graphical Abstract
Remuzzi A, Remuzzi G. CoVID-19 and Italy: what next? Lancet 2020; 395(10231): 1225-8.
[] [PMID: 32178769]
National Disaster Management Agency. Data Sebaran CoVID-19. 2020. Available at:
WHO. Novel coronavirus – China. 2020. Available at: http://www.who. int/csr/don/12-january-2020-novel-coronavirus-china/en/
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[] [PMID: 31986264]
Richman DD, Whitley RJ, Hayden FG. Clinical virology(4th ed) Washington ASM Press. . 2016.
Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020; 92(4): 418-23.
[] [PMID: 31967327]
Gorbalenya AE, Baker SC, Baric RS, et al. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5(4): 536-44.
[] [PMID: 32123347]
Kuiken T, Fouchier RAM, Schutten M, et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 2003; 362(9380): 263-70.
[] [PMID: 12892955]
Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367(19): 1814-20.
[] [PMID: 23075143]
de Groot RJ, Baker SC, Baric RS, et al. Middle East respiratory syndrome coronavirus (MERS- CoV): announcement of the Coronavirus Study Group. J Virol 2013; 87(14): 7790-2.
[] [PMID: 23678167]
WHO. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003. 2003. Available at: https://www.
WHO. Middle East respiratory syndrome coronavirus (MERS- CoV). 2019. Available at:
Meo SA, Alhowikan AM, Al-Khlaiwi T, et al. Novel coronavirus 2019-nCoV: prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV. Eur Rev Med Pharmacol Sci 2020; 24(4): 2012-9.
[PMID: 32141570]
Zhang D-H, Wu K-L, Zhang X, Deng SQ, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med 2020; 18(2): 152-8.
[] [PMID: 32113846]
Yang Y, Islam MS, Wang J, Li Y, Chen X. Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. Int J Biol Sci 2020; 16(10): 1708-17.
[] [PMID: 32226288]
Wang C, Dai Y, Yang J, Chou G, Wang C, Wang Z. Treatment with total alkaloids from Radix Linderae reduces inflammation and joint destruction in type II collagen-induced model for rheumatoid arthritis. J Ethnopharmacol 2007; 111(2): 322-8.
[] [PMID: 17204385]
An Editorial Committee of the Administration Bureau of Traditional Chinese Medicine.Chinese Materia Medica (Zhonghua Bencao)Shanghai: Shanghai Science &Technology Press. 1999; p. 3.
Iwasa K, Moriyasu M, Tachibana Y, et al. Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents. Bioorg Med Chem 2001; 9(11): 2871-84.
[] [PMID: 11597468]
Li SY, Chen C, Zhang HQ, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67(1): 18-23.
[] [PMID: 15885816]
Tian HY. [2019-nCoV: new challenges from coronavirus]. Zhonghua Yu Fang Yi Xue Za Zhi 2020; 54(0): E001.
[PMID: 32023682]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[] [PMID: 32015507]
Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature 2009; 458(7237): 430-7.
[] [PMID: 19325622]
Isaacson MK, Ploegh HL. Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe 2009; 5(6): 559-70.
[] [PMID: 19527883]
Mukherjee P, Shah F, Desai P, Avery M. Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. J Chem Inf Model 2011; 51(6): 1376-92.
[] [PMID: 21604711]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[] [PMID: 14647384]
Hardjono S. Sintesis dan uji aktivitas antikanker senyawa 1-(2—klorobenzoiloksi) urea dan 1-(4-klorobenzoiloksi) urea. Berkala Ilmiah Kimia Farmasi 2013; 2(1): 1.
Wen CC, Kuo YH, Jan JT, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007; 50(17): 4087-95.
[] [PMID: 17663539]
Ryu YB, Park SJ, Kim YM, et al. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii. Bioorg Med Chem Lett 2010; 20(6): 1873-6.
[] [PMID: 20167482]
Park JY, Kim JH, Kim YM, et al. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem 2012; 20(19): 5928-35.
[] [PMID: 22884354]
Park JY, Kim JH, Kwon JM, et al. Dieckol, a SARS-CoV 3CL(pro) inhibitor, isolated from the edible brown algae Ecklonia cava. Bioorg Med Chem 2013; 21(13): 3730-7.
[] [PMID: 23647823]
Song YH, Kim DW, Curtis-Long MJ, et al. Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits. Biol Pharm Bull 2014; 37(6): 1021-8.
[] [PMID: 24882413]
Park JY, Ko JA, Kim DW, et al. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem 2016; 31(1): 23-30.
[] [PMID: 25683083]
Shen L, Niu J, Wang C, et al. High-throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses. J Virol 2019; 93(12): e00023-19.
[] [PMID: 30918074]
Nakamura Y, Asahi H, Altaf Ul Amin, et al. KNApSAcK: a comprehensive species-metabolite relationship database. 2020. Available at: /KNApSAcK/
National Center for Biotechnology Information. PubChem Database. 2020. Available at:
National Center for Biotechnology Information. Protein. 2020. Available at: https://
Bertoni M, Kiefer F, Biasini M, Bordoli L, Schwede T. Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology. Sci Rep 2017; 7(1): 10480.
[] [PMID: 28874689]
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): 455-61.
[PMID: 19499576]
Gan LS, Yao W, Mo JX, Zhou CX. Alkaloids from Lindera aggregata. Nat Prod Commun 2009; 4(1): 43-6.
[] [PMID: 19370873]
Gan LS, Zhao X, Yao W, et al. A novel bisbenzylisoquinoline alkaloid from Lindera aggregata. J Chem Res 2008; 285-6.
Knegtel RM, Grootenhuis PD. Binding affinities and non-bonded interaction energies. Perspect Drug Discov 1998; 9: 99-114.
Tomita M, Sawada T, Kozuka M. Alkaloids of Lindera strychnifolia and Lindera umbellata. Yakugaku Zasshi 1969; 89: 737-40.
[] [PMID: 5818014]
Kozuka M, Yoshikawa M, Sawada T. Alkaloids from Lindera strychnifolia. J Nat Prod 1984; 47(6): 1063.
[] [PMID: 6533267]
Chou GX, Norio N, Ma CM, et al. Isoquinoline alkaloids from Lindera aggregata. Chin J Nat Med 2005; 3: 272-5.
Li JB, Ding Y, Li WM. A new sesquiterpene from the roots of Lindera strychnifolia. Chin Chem Lett 2002; 13: 965-7.
Zhang CF, Sun QS, Chou GX, Wang ZT. Studies on the flavonoids from leaves of Lindera aggregata Kosterm. J Shenyang Pharm Univ 2003; 20: 342-4.
Zhang CF, Chou GX, Sun QS, et al. Tannins from the stems of Lindera aggregata. Chin J Nat Med 2003; 1: 204-6.
Deng Y, Li Y. Linderalactone inhibits human lung cancer growth by modulating the expression of apoptosis-related proteins, G2/M cell cycle arrest and inhibition of JAK/STAT signalling pathway. J BUON 2019; 24(2): 566-71.
[PMID: 31128007]
Xie W, Ye Y, Feng Y, et al. Linderane suppresses hepatic gluconeogenesis by inhibiting the cAMP/PKA/CREB pathway through indirect activation of PDE 3 via ERK/STAT3. Front Pharmacol 2018; 9: 476.
[] [PMID: 29867482]
Zhang H, Zhu C, Sun Z, et al. Linderane protects pancreatic β cells from streptozotocin (STZ)-induced oxidative damage. Life Sci 2019; 233: 116732.
[] [PMID: 31394125]
Zahari A, Cheah FK, Mohamad J, et al. Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata. Planta Med 2014; 80(7): 599-603.
[] [PMID: 24723007]
Wang J, Wang F, Yuan L, et al. Aqueous extracts of Lindera aggregate (Sims) Kosterm leaves regulate serum/hepatic lipid and liver function in normal and hypercholesterolemic mice. J Pharmacol Sci 2020; 143(1): 45-51.
[] [PMID: 32169433]
Gu L, Luo Q, Xiao M, et al. Anti-oxidative and hepatoprotective activities of the total flavonoids from the leaf of Lindera aggregate (Sim) Kosterm against mice liver injury induced by carbon tetrachloride. Zhongyao Xinyao Yu Linchuang Yaoli 2018; 19: 447-50.
Chaofeng Z, Qishi S, Zhengtao W, et al. Inhibitory activities of tannins extracted from stem of Lindera aggregata against HIV-1 integrase. Zhongguo Zhongyao Zazhi 2003; 38(12): 911-4.
Bahmani M, Khaksarian M, Rafieian-Kopaei M, Abbasi N. Overview of the therapeutic effects of Origanum vulgare and Hyperacum perforatum based on Iran’s ethno pharmacological documents. J Clin Diagn Res 2018; 7: 1-4.
Carrillo-Galván G, Bye R, Eguiarte LE, et al. Domestication of aromatic medicinal plants in Mexico: Agastache (Lamiaceae)-an ethnobotanical, morpho-physiological, and phytochemical analysis. J Ethnobiol Ethnomed 2020; 16(1): 22.
[] [PMID: 32357896]
Ejeta D. Ethno-botanical Survey of plants used for prevention against mosquito bites and control of malaria in Assosa district, Western Ethiopia. J Ethnobiol Ethnomed 2019; 6: 1.
Silalahi M. Nisyawati. The ethnobotanical study of edible and medicinal plants in the home garden of Batak Karo sub-ethnic in North Sumatra, Indonesia. Biodiversitas (Surak) 2018; 19: 229-38.
Himmi SK, Humaedi MA, Astutik S. Ethnobiological study of the plants used in the healing practices of an indigenous people Tau Taa Wana in Central Sulawesi, Indonesia. Procedia Environ Sci 2014; 20: 841-6.
Raefieian-Kopaei M, Karami N, Abbaszadeh S, et al. Medicinal plants for treatment kidney stones, an ethnobotany study in Shahrekord. Egypt J Vet Sci 2019; 50(2): 145-9.
Wu Z, Raven PH. Flora of China St Louis Science Press and Beijing & Missouri Botanical Garden Press. 2008; p. 7.
Hong L, Guo Z, Huang K, et al. Ethnobotanical study on medicinal plants used by Maonan people in China. J Ethnobiol Ethnomed 2015; 11: 32.
[] [PMID: 25925830]
Ruehl M, Erben U, Kim K, et al. Extracts of Lindera obtusiloba induce antifibrotic effects in hepatic stellate cells via suppression of a TGF-β-mediated profibrotic gene expression pattern. J Nutr Biochem 2009; 20(8): 597-606.
[] [PMID: 18824344]
Cao Y, Xuan B, Peng B, et al. The genus Lindera: a source of structurally diverse molecules having pharmacological significance. Phytochem Rev 2016; 15: 869-906.
Manandhar NP, Manandhar S. Plants and People of NepalPortland: Timber Press, Inc. 2002.
Wang JW, Chen XY, Hu PY, et al. Effects of Linderae radix extracts on a rat model of alcoholic liver injury. Exp Ther Med 2016; 11(6): 2185-92.
[] [PMID: 27313665]
Yan R, Yang Y, Zeng Y, Zou G. Cytotoxicity and antibacterial activity of Lindera strychnifolia essential oils and extracts. J Ethnopharmacol 2009; 121(3): 451-5.
[] [PMID: 18602979]
Shimomura M, Ushikoshi H, Hattori A, et al. Treatment with Lindera strychnifolia reduces blood pressure by decreasing sympathetic nerve activity in spontaneously hypertensive rats. Am J Chin Med 2010; 38(3): 561-8.
[] [PMID: 20503472]
Xu C, Yang B, Zhu W, Li X, Tian J, Zhang L. Characterisation of polyphenol constituents of Linderae aggregate leaves using HPLC fingerprint analysis and their antioxidant activities. Food Chem 2015; 186: 83-9.
[] [PMID: 25976795]
Hosseinzadeh M, Hadi AH, Mohamad J, Khalilzadeh MA, Cheahd SC, Fadaeinasab M. Flavonoids and linderone from Lindera oxyphylla and their bioactivities. Comb Chem High Throughput Screen 2013; 16(2): 160-6.
[PMID: 23173924]
Information System of Living Collections Catalog of Purwodadi Botanic Garden. 2020. Available at:

© 2024 Bentham Science Publishers | Privacy Policy