Document Type : Original Article


1 Department of Biology, Faculty of Mathematics and Natural Science, University of Brawijaya, Malang, Indonesia

2 Animal Physiology and Molecular Laboratory, Department of Biology, University of Brawijaya, Malang, Indonesia

3 Plant Genetics and Physiology Laboratory, Department of Biology, University of Brawijaya, Malang, Indonesia


Background: Plant-based remedies against Covid-19 and their research to discover antiviral compounds have been growing rapidly. However, there are little interest to explore and collect information of bioactive compounds of pepper (Capsicum sp.) to fight off the disease. This study aimed to bioinformatically explore and identify bioactive compounds in chili pepper fruits from four Capsicum species (C. annuum, C. baccatum, C. chinense, C. frutescens) which were compatible to fight off SARS-CoV-2 and provide indirect and direct virus inhibition from previous studies.
Methods: Protein-ligand interactions were obtained from protein data bank (PDB), PubChem, and SwissModel for homology modeling. Docking was performed using PyRx and visualized using BIOVIA Discovery Studio Visualizer 2016.
Results: Four chili pepper species were rich in organic acid compounds (100 times higher than carotenoids concentration; 0.2-156 mg/kg F.W). A type of fatty acids composition in seeds was slightly different from flesh and peels by the small amount of pharmaceutically valuable palmitoleic acids in seeds (approximately 30 mg/kg F.W). Composition of flavonoid relatively varied among the species but luteolin was found in all chili peppers (0.5-18 mg/kg F.W). Most of the compounds were actively interacting with 3CLPro rather than ACE-2 and TMPRSS2 which were well covered up by only 10 and 17 molecules respectively.
Conclusion: Four chili pepper species contained bioactive compounds that are medicinally important to fight against SARS-CoV-2 infection.

Graphical Abstract

Bioinformatics Analysis of Bioactive Compounds of Four Capsicum Species against SARS-CoV-2 Infection


Key messages:

  1. Implication for policy makers
  • Nowadays, price of chili pepper in Indonesia has been unstable and introducing the medicinal value to fight off SARS-CoV-2 infection can trigger and soon standardize pepper price.
  • Capsicum annuum that consists the highest number of superior varieties planted in Indonesia, can be tolerant to certain stress agents (physical, chemical, biological stress sources). It can be expected to supply chili pepper which is valuable to counter attack covid-19 spread.
  1. Implication for public

Herb-based crop, such as chili pepper (Capsicum sp.), which is well known due to the attribute of spiciness and flavor, can be a promising source for the supply of drugs production. By applying bioinformatics analysis to discover potential compounds in chili pepper, 17 new compounds in chili pepper, except from fatty acids, were bioinformatically matched with all proteins tested, namely human-based (ACE-2 and TMPRSS2) and viral protein (3CLPro) which plays a crucial part in SARS CoV-2 infection. Some carotenoids in chili pepper were potentially as either antioxidant or powerful SARS-CoV-2-cell interaction blockage. Among four species investigated, C. annuum is the highest in carotenoids and fatty acids while flavonoid and organic acids in C. chinense.



Main Subjects

[1]       Singhal T. (2020). A Review of Coronavirus Disease-2019 (COVID-19). Indian J. Pediatr., 87(4):281-286.
[2]       Zhou P, Yang XL, Wang XG, Hua Y, Li L. (2020). Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. Microbiology,
[3]       Liu P, Jiang JZ, Wan XF, Hua L. (2020). Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? PLOS Pathog., 16(5): e1008421.
[4]       Chan KH, Peiris JSM, Lam SY, Poon LLM, Yuen KY, Seto WH. (2011). The effects of temperature and relative humidity on the viability of the SARS Coronavirus. Adv. Virol., 1-7.
[5]       Jayaweera M, Perera H, Gunawardana B, Manatunge J. (2020). Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ. Res., 188: 109819.
[6]       Worldometer, "Covid-19 Coronavirus Pandemic," accessed on October 4th 2020
[7]       Glowacka I, Bertram S, Muller MA, Allen P, Soilleux  E, Pfefferle  S. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J. Virol., 85(9): 4122-4134.
[8]       Kawase M, Shirato K, van der Hoek L, Taguchi F, Matsuyama S. (2012). Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome Coronavirus entry. J. Virol., 86(12):6537-6545.
[9]       Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. (2019). TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J. Virol., 93(6): e01815-18.
[10]     Tahirul Qamar M, Alqahtani SM, Alamri MA, Chen LL. (2020). Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J. Pharm. Anal., 10(4): 313-319.
[11]     Sa Ribero M, Jouvenet N, Dreux M, Nisole S. (2020). Interplay between SARS-CoV-2 and the type I interferon response. PLOS Pathog, 16(7): e1008737.
[12]     Shaheen MNF, Abd El-Daim SE, Ahmed NI, Elmahdy EM. (2020). Environmental monitoring of Aichi virus and human bocavirus in samples from wastewater treatment plant, drain, and River Nile in Egypt. J. Water Health, 18(1): 30-37.
[13]     Zanwar AA, Badole SL, Shende PS, Hegde MV, Bodhankar SL. (2014). Cardiovascular Effects of Hesperidin. In: Polyphenols in Human Health and Disease, Elsevier; 989-992.
[14]     Gertsch J, Pertwee RG, Di Marzo V. (2010). Phytocannabinoids beyond the Cannabis plant - do they exist?: Phytocannabinoids beyond the Cannabis plant. Br. J. Pharmacol., 160(3): 523-529.
[15]     Tallei TE, Tumilaar SG, Niode NJ, Fatimawati F, Kepel J, Idroes R, et al. (2020). Potential of plant bioactive compounds as SARS-CoV-2 Main Protease (Mpro) and spike (S) glycoprotein inhibitors: A molecular docking study. Med. Pharmacol., Preprint.
[16]     Ekasari W, Widya Pratiwi D, Amanda Z, Suciati, Widyawaruyanti A, Arwati H. (2019). Various parts of Helianthus annuus plants as new sources of antimalarial drugs. Evid. Based Complement. Alternat. Med., 2019: 1-7.
[17]     Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. (2004). Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J. Virol., 78(20): 11334-11339.
[18]     Verschueren KHG, Pumpor K, Anemüller S, Chen S,  Mesters JR, Hilgenfeld R. (2008). A structural view of the inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters. Chem Biol, 15(6): 597–606.
[19]     Braga CB, Martins AC, Cayotopa ADE, Klein WW, Schlosser AR, Silva AF. (2015).  Side effects of chloroquine and primaquine and symptom reduction in malaria endemic area (Mâncio Lima, Acre, Brazil) (pp.1-7). Interdis. Perspect. Infect. Dis.
[20]     Food and Agriculture Organiztion of The United Nations (FAO). (1999). Strategies for sustainment of nutrition and immune function in the field. National Academies Press, Washington, D. C .
[21]     Barbero GF, Liazid A, Azaroual L, Palma M, Barroso CG. (2016). Capsaicinoid contents in peppers and pepper-related spicy foods. Int. J. Food Prop., 19(3): 485–493.
[22]     Saleh BK, Omer A, Teweldemedhin B. (2018). Medicinal uses and health benefits of chili pepper (Capsicum spp.): A review. MOJ Food Process Technol., 6(4): 325-328.
[23]     Bosland WP. (1996). Capsicums. Innovative uses of an ancient crop. In: Janick J (eds), Progress in New Crops. ASHS Press, Arlington, VA, pp. 479-487.
[24]     Meghvansi MK, Siddiqui S, Khan MH, Gupta VK, Vairale MG, Gogoi HK. (2010). Naga chilli: A potential source of capsaicinoids with broad-spectrum ethnopharmacological applications. J. Ethnopharmacol., 132(1): 1–14.
[25]     Ordaz-Trinidad N, Dorantes-Álvarez L, Salas-Benito J, Barrón-Romero BL, Salas-Benito M, Nova-Ocampo MD. (2018). Cytotoxicity and antiviral activity of pepper extracts (Capsicum spp). Polibotánica, 46: 273-285.
[26]     Stahl W, Sies H. (2003). Antioxidant activity of carotenoids. Mol. Aspects Med., 24(6): 345–351.
[27]     Young A, Lowe G. (2018). Carotenoids-antioxidant properties. Antioxidants, 7(2): 28.
[28]     Bayat A. (2002). Science, medicine, and the future: Bioinformatics. BMJ, 324(7344): 1018–1022.
[29]     Vera-Guzmán AM, Aquino-Bolaños EN, Heredia-García E, Carrillo-Rodríguez JC, Hernández-Delgado S, Chávez-Servia JL. (2017). Flavonoid and capsaicinoid contents and consumption of mexican chili pepper (Capsicum annuum L.) Landraces. in Justino GC (Eds), Flavonoids - From Biosynthesis to Human Health. InTech.
[30]     Zimmer AR, Leonardi B, Miron D, Schapoval E, de Oliveira JR, Gosmann G. (2012). Antioxidant and anti-inflammatory properties of Capsicum baccatum: From traditional use to scientific approach. J. Ethnopharmacol., 139(1): 228–233.
[31]     Howard LR, Talcott ST, Brenes CH, and Villalon B. (2000). Changes in phytochemical and antioxidant activity of selected pepper cultivars (Capsicum species) as influenced by Maturity. J. Agric. Food Chem, 4895): 1713–1720.
[32]     Kuna A, Sahoo MR, Sowmya M, Devi MP, Dasgupta M, Sreedar M, Tholemfhuang S. (2018). Nutrient and antioxidant properties of value added king chilli (Capsicum chinense) products. Int. J. Curr. MIcrobiol. Appl. Sci., 7(5): 1-8.
[33]     Suzuki K, Mori M, Ishikawa K, Takizawa K, Nunomura O. (2007). Carotenoid composition in mature Capsicum annuum. Food Sci. Technol. Res., 13(1): 77–80.
[34]     Mohd Hassan N, Yusof NA, Yahaya AF, Mohd Rozali NN, Othman R. (2019). Carotenoids of Capsicum fruits: Pigment profile and health-promoting functional attributes.  Antioxidants,  8(10): 469.
[35]     Wahyuni Y, Ballester AR, Sudarmonowati E, Bino RJ, Bovy AG. (2011). Metabolite biodiversity in pepper (Capsicum) fruits of thirty-two diverse accessions: Variation in health-related compounds and implications for breeding. Phytochemistry, 72(11–12): 1358–1370. doi: 10.1016/j.phytochem.2011.03.016.
[36]     Lim KT. (2013). Edible medicinal and non-medicinal plants: Volume 6, fruits (pp. 207-122): Springer.
[37]     Denev P, Todorova V, Ognyanov M, Georgiev Y, Yanakieva I, Tringovska I, Grozeva S, Kostova D. (2019). Phytochemical composition and antioxidant activity of 63 Balkan pepper (Capsicum annuum L.) accessions.  J Food Measure Characterization, 13(4): 2510–2520.
[38]     Manikharda, Takahashi M, Arakaki M, Yonamine K, Asikin Y, Takara K, Wada K. (2007). Physical properties, flavor characteristics and antioxidant capacity of Shimatogarashi (Capsicum frutescens). Food Sci Technol Res, 23(3): 427–435.
[39]     Jarret R L, Baldwin E, Perkins B, Bushway R, Guthrie K. (2007). Diversity of fruit quality characteristics in Capsicum frutescens. Hort. Sci., 42(1): 16–19.
 [40]    Albrecht E, Stommel J, Saftner R (2010). Variability of free sugars, organic acids and capsaicinoids in Capsicum baccatum. 2010 ASHS Annual Conference. Palm Desert, CA. 3834. Retrieved from
[41]     Kantar MB, Anderson JE, Lucht SA, Mercer K, Bernau V, Case KA, et al. (2016). Vitamin variation in Capsicum spp. provides opportunities to improve nutritional value of human diets. PLoS ONE, 11(8).
[42]     Sora GTS, Souza AHP, Fielinski AAF, Haminiuk CWI, Matsushita M, Peralta RM. (2015). Fatty acid composition of Capsicum genus peppers. Cienc. Agrotec. Lavras, 39(4): 372-380.
[43]     Khaerunnisa S, Kurniawan H, Awaluddin R, huhartati S, Soetjipto S. (2020). Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Med. Pharmacol., 1-14.
[44]     Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, et al. (2020). Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: An in silico study for drug development. J. Biomol. Struct. Dyn., 1-11.
[45]     Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, et al. (2012). Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg. Med. Chem. Lett., 22 (12): 4049–4054.
[46]     Kim HW, Chew BP, Wong TS, Park JS, Weng BB, Bryne KM, et al. (2000). Dietary lutein stimulates immune response in the canine. Vet. Immunol. Immunopathol., 74 (3–4): 315–327.
[47]     Hughes DA. (1999). Effects of carotenoids on human immune function. Nutrition, 17(10): 823-827.
[48]     Kim J, Lee J, Oh JH, Chang HJ, Sohn DK, Kwon O, et al. (2019). Dietary lutein plus zeaxanthin intake and DICER1 rs3742330 A > G polymorphism relative to colorectal cancer risk. Sci. Rep., 9(1): 1-8.
[49]     Greatorex JS, Page RF, Curran MD, Digard P, Estone JE, Wreghitt T, et al. (2010). Effectiveness of common household cleaning agents in reducing the viability of human influenza A/H1N1. PLoS ONE, 5(2): 1-5.
[50]     Poli G, Bondi PA, Uberti F, Ponti W, Balsari A, Cantoni C. (1979). Virucidal activity of organic acids. Food Chem., 4(4): 251–258.
[51]     Willis MD, Robertson NP. (2020) Multiple sclerosis and the risk of infection: Considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2. J. Neurol., 267(5): 1567–1569.
[52]     Keiran N, Mallafre VC, Calvo E, Hernandez-Alvarez MI, Ejarque M, Nunez-Roa C, et al. (2019). SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat. Immunol., 20(5): 581–592.
[53]     Boretti A, Banik BK. (2020). Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition, 12: 100190.
[54]     Sheybani Z, Dokoohaki MH, Negahdaripour M, Dehdashti M, Moghadami M, Masoompour SM, et al. (2020). The role of folic acid in the management of respiratory disease caused by COVID-19. ChemRxiv.
[55]     Gonzalez-Paz LA, Lossada CA, Moncayo LS, Romero F, Paz JL, Vera-Villalobos J, et al. (2020). Theoretical molecular docking study of the structural disruption of the Viral 3CL-Protease of COVID19 induced by binding of capsaicin, piperine and curcumin part 1: A comparative study with chloroquine and hydrochloroquine two antimalaric drugs. Compt. Chem.
[56]     Das UN. (2020). Can bioactive lipids inactivate coronavirus (COVID-19)?. Arch. Med. Res., 51(3): 282–286. https://doi/org/10.1016/j.arcmed.2020.03.004.
[57]     Baskaran P, Covington K, Bennis J, Mohandass A,Lehmann T, Thyagarajan B. (2018). Binding efficacy and thermogenic efficiency of pungent and nonpungent analogs of capsaicin. Molecules, 23(12): 3198. 2018.
[58]     Chamikara MDM, Dissanayake DRRP, Ishan M, Sooriyapathirana SDSS. (2016). Dietary, anticancer and medicinal properties of the phytochemicals in chili pepper (Capsicum spp.). Ceylon J. Sci., 45(3): 5-20).
[59]     Marini E, Magi G, Mingoia M, Pugnaloni A, Facinelli B. (2015). Antimicrobial and anti-virulence activity of capsaicin against erythromycin-resistant, cell-invasive group a streptococci. Front. Microbiol., 6: 1281.
[60]     Hafiz TA, Mubaraki MA, Dkhil MA, Al-Quraishy S. (2017). Antiviral activities of Capsicum annuum methanolic extract against Herpes Simplex Virus 1 and 2. Pak. J. Zool., 49(1): 251–255.
[61]     Tang K, Zhang X, Guo Y. (2020). Identification of the dietary supplement capsaicin as an inhibitor of Lassa virus entry. Acta Pharm. Sin. B., 10(5): 789–798.
[62]     Wu C, Liu Y, Yang Y, Zhong W, Wang Y, Wang Q, et al., (2020). Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B., 10(5): 766–788.
[63]     Xia S, Zhu Y, Liu M, Lan Q, Xu W, Wu Y, et al. (2020). Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cell. Mol. Immunol., 17(7): 765–767.
[64]     Hussain M, Jabeen N, Amanullah A, Baig AA, Aziz B, Shabbir S, et al. (2020) Structural basis of SARS-CoV-2 Spike Protein priming by TMPRSS2. AIMS Microbiology, 6(3): 350-360.
[65]     Grum-Tokars V, Ratia K, Begaye A, Baker SC, Mesecar AD. (2008). Evaluating the 3C-like protease activity of SARS-Coronavirus: Recommendations for standardized assays for drug discovery. Virus Res., 133(1): 63–73.
[66]     Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. (2016). An overview of severe acute respiratory syndrome–coronavirus (SARS-CoV) 3CL protease inhibitors: Peptidomimetics and small molecule chemotherapy. J. Med. Chem., 59(14): 6595–6628.
[67]     Chen CJ, Michael M, Hsu HK, Tsai CC, Yang KD, Wu YC, et al. (2008). Toona sinensis Roem tender leaf extract inhibits SARS coronavirus replication. J.  Ethnopharmacol., 120(1): 108-111.
[68]     Deng YF, Aluko RE, Jin Q, Zhang Y, Yuan LJ. (2012). Inhibitory activities of baicalin against renin and angiotensin-converting enzyme. Pharm. Biol., 50(4): 401-406.
 [69]    Pang R, Jun-Yan T, Shu-Ling, Z, Lei, Z, Xin, Y, Yue-Feng, W, et al. (2010). In vitro antiviral activity of lutein against hepatitis B virus. Phytother. Res., 24(11): 1627-1630.
[70]     Háda M, Nagy V, Deli J, Agócs A. (2012). Hydrophilic carotenoids: Recent progress. Molecules, 17(5): 5003–5012.
[71]     Pantsar T, Poso A. (2018). Binding affinity via docking: Fact and fiction. Molecules, 23(8): 1899.
[72]     Otto S, Engberts JBFN. (2003). Hydrophobic interactions and chemical reactivity. Org. Biomol. Chem., 1: 2809-2820.
[73]     Wibowo S, Widyarti S, Sabarudin A, Soeatmadji DW, Sumitro SB. (2019). The the role of astaxanthin compared with metformin in preventing glycated human serum albumin from possible unfolding: A molecular dynamic study. Asian J. Pharm. Clin. Res., 12(9): 276–282.