Bioactive Compound Profile and Biological Modeling Reveals the Potential Role of Purified Methanolic Extract of Sweet Flag ( Acorus calamus  L.) in Inhibiting the Dengue Virus (DENV) NS3 Protease-Helicase

Yuli Arif Tribudi; Ayu Tri Agustin; Dian Eka Setyaningtyas; Dwi Gusmalawati

doi:10.22146/ijc.68317

Bioactive Compound Profile and Biological Modeling Reveals the Potential Role of Purified Methanolic Extract of Sweet Flag (Acorus calamus L.) in Inhibiting the Dengue Virus (DENV) NS3 Protease-Helicase

https://doi.org/10.22146/ijc.68317

Yuli Arif Tribudi^(1*), Ayu Tri Agustin⁽²⁾, Dian Eka Setyaningtyas⁽³⁾, Dwi Gusmalawati⁽⁴⁾

(1) Department of Animal Science, Faculty of Agriculture, Tanjungpura University, Jl. Prof. Hadari Nawawi, Pontianak 78121, West Kalimantan, Indonesia
(2) Medical Laboratory Technology Study Program, Politeknik Yakpermas Banyumas, Jl. Raya Jompo Kulon Sukoraja, Banyumas 53181, Indonesia
(3) National Research and Innovation Agency (BRIN), Jl. Raya Jakarta-Bogor, Cibinong, Bogor 16915, West Java, Indonesia
(4) Department of Biology, Faculty of Mathematics and Natural Sciences, Tanjungpura University, Jl. Prof. Hadari Nawawi, Pontianak 78121, West Kalimantan, Indonesia
(*) Corresponding Author

Abstract

Dengue fever is an infectious disease caused by the dengue virus, and there is no yet effective drug to treat this disease successfully. Our study aimed to identify the bioactive compounds of Acorus calamus L. and its potential role in inhibiting dengue virus NS3 protease-helicase. Liquid Chromatography-Mass Spectrometry analyzed phytochemical constituents. Drug-likeness of the predominant compound methanol extract of Acorus calamus L. was investigated through the SWISS ADME server. Complex molecular interactions were investigated by Hex 8.0 docking program and Discovery studio 2016. Our study revealed that the five largest phytochemicals in the extract were acoric acid, acorone, acoradin, acoronene, and calamendiol. All predominant compounds are potent to be developed as drug candidates. Molecular docking results showed that the five compounds bind to the Arg599, Pro291, Lys388, Pro431, and His487 of the dengue virus NS3 protease-helicase, the ligand-binding site that plays an essential role in viral replication. The ligand-protein binding pattern exhibited hydrogen and hydrophobic interactions. The interaction of the acoradin-NS3 protease-helicase complex had the lowest binding energy of -299.7 kcal/mol. In summary, we conclude that Acorus calamus L. extract may have prospects as a drug for dengue virus infection.

Keywords

bioactivity; dengue viral infection; herb medicine; LC-MS; in silico

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References

[1] Zahid, K., Shakoor, S., Sajid, H.A., Afzal, S., Ali, L., Amin, I., Shahid, M., and Idrees, M., 2020, Advancements in developing an effective and preventive dengue vaccine, Future Virol., 15 (2), 127–138.

[2] Bhatt, P., Sabeena, S.P., Varma, M., and Arunkumar, G., 2021, Current understanding of the pathogenesis of dengue virus infection, Curr. Microbiol., 78 (1), 17–32.

[3] Rosmalena, R., Elya, B., Dewi, B.E., Fithriyah, F., Desti, H., Angelina, M., Hanafi, M., Lotulung, P.D., Prasasty, V.D., and Seto, D., 2019, The antiviral effect of Indonesian medicinal plant extracts against dengue virus in vitro and in silico, Pathogens, 8 (2), 85.

[4] Halim, S.A., Khan, S., Khan, A., Wadood, A., Mabood, F., Hussain, J., and Al-Harrasi, A., 2017, Targeting dengue virus NS-3 helicase by ligand based pharmacophore modeling and structure based virtual screening, Front. Chem., 5, 88.

[5] Obi, J.O., Gutiérrez-Barbosa, H., Chua, J.V., and Deredge, D.J., 2021, Current trends and limitations in dengue antiviral research, Trop. Med. Infect. Dis., 6 (4), 180.

[6] Luo, D., Wei, N., Doan, D.N., Paradkar, P.N., Chong, Y., Davidson, A.D., Kotaka, M., Lescar, J., and Vasudevan, S.G., 2010, Flexibility between the protease and helicase domains of the dengue virus NS3 protein conferred by the linker region and its functional implications, J. Biol. Chem., 285 (24), 18817–18827.

[7] Basavannacharya, C., and Vasudevan, S.G., 2014, Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format, Biochem. Biophys. Res. Commun., 453 (3), 539–544.

[8] Rather, I.A., Parray, H.A., Lone, J.B., Paek, W.K., Lim, J., Bajpai, V.K., and Park, Y.H., 2017, Prevention and control strategies to counter dengue virus infection, Front. Cell. Infect. Microbiol., 7, 336.

[9] Elshikh, M.S., Rani, E., Al Farraj, D.A., Al-Hemaid, F.M.A., Abdel Gawwad, M.R., Jeba Malar, T.R.J., Dyona, L., and Vijayaraghavan, P., 2022, Plant secondary metabolites extracted from Acorus calamus rhizome from Western Ghats, India and repellent activity on Sitophilus oryzae, Physiol. Mol. Plant Pathol., 117, 101743.

[10] Vadivel, V., Kausalya, J., Vidhyalakshmi, S., Sriram, S., Rajalakshmi, P., and Brindha, P., 2017, Phytochemical levels and antioxidant activity of traditionally processed Indian herbal mixture (Acorus calamus, Curcuma aromatica and Zingiber officinale), Trop. J. Nat. Prod. Res., 1 (6), 262–269.

[11] Chaubey, P., Archana, Prakash, O., Rai, K., Kumar, R., and Pant, A.K., 2017, In vitro antioxidant activity and total phenolic content of rhizome extracts from Acorus calamus Linn, Asian J. Chem., 29 (11), 2357–2360.

[12] Iancu, I.M., Bucur, L.A., Schroder, V., Mireșan, H., Sebastian, M., Iancu, V., and Badea, V., 2021, Phytochemical evaluation and cytotoxicity assay of Lythri herba extracts, Farmacia, 69 (1), 51–58.

[13] Gusmalawati, D., Arumingtyas, E.L., Azrianingsih, R., and Mastuti, R., 2019, LC-MS analysis of carbohydrate components in Porang tubers (Amorphophallus muelleri Blume) from the second and the third growth period, IOP Conf. Ser.: Earth Environ. Sci., 391, 012022.

[14] Agustin, A.T., Safitri, A., and Fatchiyah, F., 2021, Java red rice (Oryza sativa L.) nutritional value and anthocyanin profiles and its potential role as antioxidant and anti-diabetic, Indones. J. Chem., 21 (4), 968–978.

[15] Lehotay, S.J., 2017, Utility of the summation chromatographic peak integration function to avoid manual reintegrations in the analysis of targeted analytes, LCGC North Am., 35 (6), 391–402.

[16] Agustin, A.T., Safitri, A., and Fatchiyah, F., 2020, An in silico approach reveals the potential function of cyanidin-3-o-glucoside of red rice in inhibiting the advanced glycation end products (AGES)-receptor (RAGE) signaling pathway, Acta Inform. Med., 28 (3), 170–179.

[17] Sivaraman, D., and Pradeep, P.S., 2020, Exploration of bioflavonoids targeting dengue virus NS5 RNA-dependent RNA polymerase: In silico molecular docking approach, J. Appl. Pharm. Sci., 10 (5), 16–22.

[18] Zubair, M.S., Anam, S., Maulana, S., and Arba, M., 2021, In vitro and in silico studies of quercetin and daidzin as selective anticancer agents, Indones. J. Chem., 21 (2), 310–317.

[19] Hermes, L., Römermann, J., Cramer, B., and Esselen, M., 2021, Quantitative analysis of β-asarone derivatives in Acorus calamus and herbal food products by HPLC-MS/MS, J. Agric. Food Chem., 69 (2), 776–782.

[20] Sidana, A., and Farooq, U., 2015, Evaluation of antileishmanial activity of plants used in Indian traditional medicine, Bangladesh J. Pharmacol., 10 (2), 423–426.

[21] Kurnianingsih, N., Ratnawati, R., Nazwar, T., Ali, M., and Fatchiyah, F., 2021, Purple sweet potatoes from East Java of Indonesia revealed the macronutrient, anthocyanin compound and antidepressant activity candidate, Med. Arch., 75 (2), 94–100.

[22] Li, J., Zhao, J., Wang, W., Li, L., Zhang, L., Zhao, X.F., Liu, Q.R., Liu, F., Yang, M., Khan, I., and Li, S.X., 2017, New acorane-type sesquiterpene from Acorus calamus L., Molecules, 22 (4), 529.

[23] Pires, D.E.V., Blundell, T.L., and Ascher, D.B., 2015, pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures, J. Med. Chem., 58 (9), 4066–4072.

[24] Berben, P., Bauer-Brandl, A., Brandl, M., Faller, B., Flaten, G.E., Jacobsen, A.C., Brouwers, J., and Augustijns, P., 2018, Drug permeability profiling using cell-free permeation tools: Overview and applications, Eur. J. Pharm. Sci., 119, 219–233.

[25] Wang, J., Ge, Y., and Xie, X.Q., 2019, Development and testing of druglike screening libraries, J. Chem. Inf. Model., 59 (1), 53–65.

[26] Benet, L.Z., Hosey, C.M., Ursu, O., and Oprea, T.I., 2016, BDDCS, the rule of 5 and drugability, Adv. Drug Delivery Rev., 101, 89–98.

[27] Zhang, Z., Fan, F., Luo, W., Zhao, Y., and Wang, C., 2020, Molecular dynamics revealing a detour-forward release mechanism of tacrine: Implication for the specific binding characteristics in butyrylcholinesterase, Front. Chem., 8, 730.

[28] Prasad, B.J., Sharavanan, P.S., and Sivaraj, R., 2019, Efficiency of Oryza punctata extract on glucose regulation: Inhibition of α-amylase and α-glucosidase activities, Grain Oil Sci. Technol., 2 (2), 44–48.

[29] Yao, X., Ling, Y., Guo, S., Wu, W., He, S., Zhang, Q., Zou, M., Nandakumar, K.S., Chen, X., and Liu, S., 2018, Tatanan A from the Acorus calamus L. root inhibited dengue virus proliferation and infections, Phytomedicine, 42, 258–267.

[30] Kharisma, V.D., Probojati, R.T., Murtadlo, A.A.A., Ansori, A.N.M., Antonius, Y., and Tamam, M.B., 2021, Revealing potency of bioactive compounds as inhibitor of dengue virus (DENV) NS2B/NS3 protease from sweet potato (Ipomoea batatas L.) leaves, Indian J. Forensic Med. Toxicol., 15 (1) 1627–1632.

[31] Lai, H., Teramoto, T., and Padmanabhan, R., 2014, "Construction of dengue virus protease expression plasmid and in vitro protease assay for screening antiviral inhibitors" in Dengue. Methods in Molecular Biology (Methods and Protocols), Eds. Padmanabhan, R., and Vasudevan, S., vol. 1138, Humana Press, New York, 345–360.

DOI: https://doi.org/10.22146/ijc.68317