In Silico Activity Identification of Cyclo Peptide Alkaloids from Zizyphus Spina-Christi Species Against Sars-Cov-2 Main Protease

Taufik Muhammad Fakih, Dwi Syah Fitra Ramadhan, Fitrianti Darusman


The COVID-19 has spread worldwide and become an international pandemic. The promising target for drug discovery of COVID-19 was SARS-CoV-2 Main Protease (Mpro), that has been successfully crystallized along with its inhibitor. The discovery of peptide-based inhibitors may present better options than small molecules for inhibitor SARS-CoV-2 Mpro. Natural compounds have such a wide potential and still few explored, Zizyphus spina-christi is one of the medicinal plants that have many pharmacological activities and contains a peptide compound from alkaloids class, i.e. cyclopeptide alkaloids, that is interesting to explore as SARS-CoV-2 Mpro inhibitor. The compound structure was drawn and optimized using density functional theory 3-21G method. The protein chosen was the high resolution of SARS-CoV-2 MPro receptor (1.45 Å) with PDB ID: 6WNP, in complex with boceprevir. Molecular docking simulation was performed using Autodock4 with 100 numbers of GA run, the validation methods assessed by RMSD calculation. Furthermore, the prediction of pharmacological activity spectra was carried out using the PASS Prediction server. The results showed RMSD value was 1.98 Å, this docking method was valid. The binding energy of all compounds showed better results than the native ligand (Boceprevir). The in silico PASS prediction results indicated that all compounds showed antiviral activity. Some compounds showed protease inhibitory activity, i.e Ambiphibine-H, Franganine, and Mauritine-A, and the highest Pa (Predicted activity) value showed by Mauritine-A compounds. It can be concluded that the cyclopeptide compounds of Zizyphus spina-christi were indicated to have a potential as COVID-19 therapy targeting SARS-CoV-2 Mpro.


COVID-19, SARS-CoV-2 main protease, peptide alkaloids, zizyphus spina-christi, in silico

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Anzali, S., Barnickel, G., Cezanne, B., Krug, M., Filimonov, D., & Poroikov, V. (2001) ‘Discriminating between drugs and nondrugs by prediction of activity spectra for substances (PASS).’, Journal of medicinal chemistry, 44(15), 2432–2437.

Asgarpanah, J. (2012) ‘Phytochemistry and pharmacologic properties of Ziziphus spina christi (L.) Willd.’, African Journal of Pharmacy and Pharmacology, 6(31), 2332–2339.

Backer, J. A., Klinkenberg, D. & Wallinga, J. (2020) ‘Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020.’, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 25(5).

Bell, E. W., & Zhang, Y. (2019) ‘DockRMSD: an open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism.’, Journal of Cheminformatics, 11(1), 40.

Benarba, B., & Pandiella, A. (2020) ‘Medicinal Plants as Sources of Active Molecules against COVID-19.’, Frontiers in pharmacology, 11, 1189.

Darusman, F., & Fakih, T. M. (2020) ‘Studi Interaksi Senyawa Turunan Saponin dari Daun Bidara Arab (Ziziphus spina-christi L.) sebagai Antiseptik Alami secara In Silico.’, Jurnal Sains Farmasi dan Klinis, 7(3), 229–235.

Dias, D. A., Urban, S., & Roessner, U. (2012) ‘A historical overview of natural products in drug discovery.’, Metabolites, 2(2), 303–336.

Du, Q.-S., Sun, H., & Chou, K.-C. (2007) ‘Inhibitor design for SARS coronavirus main protease based on “distorted key theory.’, Medicinal chemistry (Shariqah (United Arab Emirates)), 3(1), 1–6.

Goyal, B., & Goyal, D. (2020) ‘Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy.’, ACS combinatorial science, 22(6), 297–305.

Gurung. A. B., Ali, M. A., Lee, J., Farah, M. A., & Al-Anazi, K. M. (2020) ‘Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 M(pro) enzyme through in silico approach.’, Life sciences, 255, 117831.

Han, Y., & Král, P. (2020) ‘Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2.’, ACS nano, 14(4), 5143–5147.

Inayat-ur-Rahman, Khan, M. A., Khan, G. A., Khan, L., & Ahmad, V. U. (2001) ‘Cyclopeptide Alkaloids of Zizyphus Species.’, Journal of Chemical Society of Pakistan, 23(4), 268–277.

Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L. W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., & Yang, H. (2020) ‘Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.’, Nature, 582(7811), 289–293.

Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., & Soetjipto, S. (2020) ‘Potential Inhibitor of COVID-19 Main Protease (Mpro) from Several Medicinal Plant Compounds by Molecular Docking Study.’, Preprints, 2020030226.

Khare, P., Sahu, U., Pandey, S. C., & Samant, M. (2020) ‘Current approaches for target-specific drug discovery using natural compounds against SARS-CoV-2 infection.’, Virus research, 290, 198169.

Lagunin, A., Stepanchikova, A., Filimonov, D., & Poroikov, V. (2000) ‘PASS: prediction of activity spectra for biologically active substances.’, Bioinformatics (Oxford, England), 16(8), 747–748.

Megantara, S., Dwi U., Puspitasari, & Resmi, M. (2017) ‘Insilico study of thymoquinone as peroxisome proliferator activated receptor gamma agonist in the treatment of type 2 diabetes mellitus.’, Journal of Pharmaceutical Sciences and Research, 9(9), 1478–1482.

Mirza, M. U. & Froeyen, M. (2020) ‘Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase.’, Journal of Pharmaceutical Analysis.

Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2010) ‘AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.’, Journal of Computational Chemistry, 30(16), 2785–2791.

Ramadhan, D. S. F., Fakih, T. M., & Arfan, A. (2020) ‘Activity Prediction of Bioactive Compounds Contained in Etlingera elatior Against the SARS-CoV-2 Main Protease: An In Silico Approach.’, Borneo Journal of Pharmacy, 3(4), 235-242.

Reiner, Ž., Hatamipour, M., Banach, M., Pirro, M., Al-Rasadi, K., Jamialahmadi, T., Radenkovic, D., Montecucco, F., & Sahebkar, A. (2020) ‘Statins and the COVID-19 main protease: in silico evidence on direct interaction.’, Archives of Medical Science, 16(3), 490–496.

Rut, W., Groborz, K., Zhang, L., Sun, X., Zmudzinski, M., Pawlik, B., Wang, X., Jochmans, D., Neyts, J., Młynarski, W., Hilgenfeld, R., & Drag, M. (2020) ‘SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging.’, Nature Chemical Biology, 17(2), 222–228.

Saied, A. S., Jens G., Karl H., & Andreas B. (2008) ‘Ziziphus spina-christi (L.) Willd.: a multipurpose fruit tree.’, Genetic Resources and Crop Evolution, 55(7), 929–937.

Ullrich, S., & Nitsche, C. (2020) ‘The SARS-CoV-2 main protease as drug target.’, Bioorganic & Medicinal Chemistry Letters, 30(17), 127377.

World Health Organization (2020) ‘Weekly Operational Update on COVID-19 september 27, 2020.’, World Health Organization (WHO), (October), 1–10. Available at:

Yoshino, R., Yasuo, N., & Sekijima, M. (2020) ‘Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates.’, Scientific Reports, 10(1), 12493.

Yossef, H. E., Khedr, A. A., & Mahran, M. Z. (2011) ‘Heptoprotective activity of Zizyphus spina-christi fruits on Carbon Tetrachloride induced Hepatotoxicity in Rats.’, 9(2), 1–7.

Zhu, H., Wei, L., & Niu, P. (2020) ‘The novel coronavirus outbreak in Wuhan, China.’, Global health research and policy, 5, 6.



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