Studi In Silico Aktivitas Analog Senyawa Zizyphine dari Bidara Arab (Zizyphus spina-christi) sebagai Antivirus SARS-CoV-2 terhadap Reseptor 3CLpro

Taufik Muhammad Fakih, Firda Aulia Jannati, Annisa Meilani, Dwi Syah Fitra Ramadhan, Fitrianti Darusman


COVID-19 merupakan penyakit yang penularannya human to human yang pertama kali ditemukan di China (Kota Wuhan). Tanaman bidara arab mengandung banyak metabolit sekunder yang bermanfaat, hasil fraksinasi dari buah bidara memiliki aktivitas sebagai antivirus yang signifikan terhadap virus herpes simpleks tipe 1. Tujuan penelitian ini adalah untuk mengetahui afinitas dan interaksi antara senyawa uji Zizyphine dengan reseptor 3CLpro secara in silico. Pada penelitian ini dilakukan identifikasi aktivitas biologis menggunakan PASS prediction dan sifat fisikokimia pada senyawa uji Zizyphine menggunakan webserver Swiss-ADME. Senyawa uji Zizyphine dioptimasi secara geometris menggunakan software Quantum ESPRESSO versi 6.6. Konformasi senyawa uji Zizyphine terbaik dilanjutkan ke tahap simulasi docking terhadap reseptor 3CLpro yang telah dipisahkan dengan ligan alaminya dan telah divalidasi menggunakan software MGL Tools versi 1.5.6 yang telah dilengkapi dengan Autodock Tools versi 4.2. Berdasarkan penelitian yang telah dilakukan dapat disimpulkan bahwa senyawa uji Zizyphine C memiliki afinitas yang lebih baik dibandingkan senyawa Zizyphine A, Zizyphine F, dan Zizyphine I dengan nilai energi bebas ikatan sebesar -9,32 kcal/mol dan konstanta inhibisi 146,89 nM, sehingga senyawa Zizyphine C berpotensi sebagai agen terapi COVID-19 yang bekerja terhadap reseptor 3CLpro. Selanjutnya dari hasil analisis aktivitas biologis, keseluruhan senyawa analog Zizyphine menunjukkan potensi sebagai antivirus. Akan tetapi dari prediksi ADME, senyawa-senyawa tersebut tidak menunjukkan profil yang baik sebagai obat oral.

In Silico Study of Zizyphine Analog Compound Activity of Christ's Thorn Jujube (Zizyphus spina-christi) as SARS-CoV-2 Antivirus against 3CLpro Receptors. COVID-19 is a disease with human-to-human transmission that was first discovered in China (Wuhan City). The arabian bidara plant (Christ's Thorn Jujube) contains many useful secondary metabolites, fractionated from bidara fruit has significant antivirus activity against herpes simplex virus type 1. The purpose of this study was to determine the affinity and interaction between the Zizyphine test compound and the 3CLpro receptor through in silico. In this study, the identification of biological activity using PASS prediction and physicochemical properties of Zizyphine test compounds using the Swiss-ADME webserver. The Zizyphine test compound was optimized for geometry using Quantum ESPRESSO version 6.6 software. The conformation of the best Zizyphine test compound was continued to the docking simulation stage for the 3CLpro receptor which has been separated from its natural ligand and has been validated using MGL Tools version 1.5.6 with Autodock Tools version 4.2 software. Based on the results, it can be concluded that the test compound Zizyphine C has a better affinity than Zizyphine A, Zizyphine F, and Zizyphine I with a binding free energy value of -9.32 kcal/mol and inhibition constant of 146.89 nM. Therefore, the compound Zizyphine C has potential as a COVID-19 therapeutic agent that acts against the 3CLpro receptor. Furthermore, from the results of the analysis of biological activity, all Zizyphine analog compounds showed potential as antiviruses. However according to ADME predictions, these compounds did not show a good profile as oral drugs.


3CLpro SARS-CoV-2; Zizyphine analog; COVID-19; in silico study; Ziziphus spina-christi.

Full Text:



Abalaka, M. E., Daniyan, S. Y., and Mann, A., 2010. Evaluation of the Antimicrobial Activities of Two Ziziphus species (Ziziphus mauritiana L. and Ziziphus spinachristi L.) on some Microbial Pathogens. African Journal of Pharmacy and Pharmacology, 4(4), 135−139.

Abdelli, I., Hassani, F., Bekkel Brikci, S., and Ghalem, S., 2021. In Silico Study the Inhibition of Angiotensin Converting Enzyme 2 Receptor of COVID-19 by Ammoides verticillata Components Harvested from Western Algeria. Journal of Biomolecular Structure and Dynamics, 39(9), 1–14. doi: 10.1080/07391102.2020.1763199.

Acúrcio, R. C., Leonardo-Sousa, C., García-Sosa, A. T., Salvador, J. A., Florindo, H. F., and Guedes, R. C., 2019. Structural Insights and Binding Analysis for Determining the Molecular Bases for Programmed Cell Death Protein Ligand-1 Inhibition. Medicinal Chemistry Communications, 10(10), 1810–1818. doi: 10.1039/c9md00326f.

Al-Saeedi, A. H., Al-Ghafri, M. T. H., and Hossain, M. A., 2017. Brine Shrimp Toxicity of Various Polarities Leaves and Fruits Crude Fractions of Ziziphus Jujuba Native to Oman And Their Antimicrobial Potency. Sustainable Chemistry and Pharmacy, 5, 122–126. doi: 10.1016/j.scp.2017.03.003.

Alves, V. M., Muratov, E. N., Capuzzi, S. J., Politi, R., Low, Y., Braga, R. C., Zakharov, A. V., Sedykh, A., Mokshyna, E., Farag, S., Andrade, C. H., Kuz’Min, V. E., Fourches, D., and Tropsha, A., 2016. Alarms about Structural Alerts. In Green Chemistry, 18(16), 4348–4360. doi: 10.1039/c6gc01492e.

Daneshmand, F., Zare-Zardini, H., Tolueinia, B., Hasani, Z., and Ghanbari, T., 2013. Crude Extract from Ziziphus Jujuba Fruits, a Weapon against Pediatric Infectious Disease. Iranian Journal of Pediatric Hematology and Oncology, 3(1), 216–221.

Darusman, F. and Fakih, T. M., 2021. Comprehensive In Silico Analysis of Christinin Molecular Behaviour from Ziziphus spina-christi Leaves on Propionibacterium acnes. Pharmaceutical Sciences and Research, 8(1), 55–64. doi: 10.7454/psr.v8i1.1112.

De Jesus, M. C., Ingle, B. L., Barakat, K. A., Shrestha, B., Slavens, K. D., Cundari, T. R., and Anderson, M. E., 2014. The Role of Strong Electrostatic Interactions at the Dimer Interface of Human Glutathione Synthetase. Protein Journal, 33(5), 403–409. doi: 10.1007/s10930-014-9573-y.

Dzubak, A. L., Mitra, C., Chance, M., Kuhn, S., Jellison, G. E., Sefat, A. S., Krogel, J. T., and Reboredo, F. A., 2017. MnNiO3 Revisited with Modern Theoretical and Experimental Methods. Journal of Chemical Physics, 147(17), 174703. doi: 10.1063/1.5000847.

Fitriyani F, F., Fakih, T. M., and Tjahjono, D. H., 2020. In Silico Studies of Green Tea Catechins Against HER-2 Receptor in Breast Cancer. Current Trends in Biotechnology and Pharmacy, 14(5), 194–199. doi: 10.5530/ctbp.2020.4s.23.

Ganesh, B., Rajakumar, T., Malathi, M., Manikandan, N., Nagaraj, J., Santhakumar, A., Elangovan, A., and Malik, Y. S., 2021. Epidemiology and Pathobiology of SARS-CoV-2 (COVID-19) in Comparison with SARS, MERS: An Updated Overview of Current Knowledge and Future Perspectives. In Clinical Epidemiology and Global Health, 10, 100694. doi: 10.1016/j.cegh.2020.100694.

Giannozzi, P., Baseggio, O., Bonfà, P., Brunato, D., Car, R., Carnimeo, I., Cavazzoni, C., De Gironcoli, S., Delugas, P., Ferrari Ruffino, F., Ferretti, A., Marzari, N., Timrov, I., Urru, A., and Baroni, S., 2020. Quantum ESPRESSO toward the Exascale. Journal of Chemical Physics, 152(15), 154105. doi: 10.1063/5.0005082.

Gyebi, G. A., Ogunro, O. B., Adegunloye, A. P., Ogunyemi, O. M., and Afolabi, S. O., 2021. Potential Inhibitors of Coronavirus 3-Chymotrypsin-Like Protease (3CLpro): an In Silico Screening of Alkaloids and Terpenoids from African Medicinal Plants. Journal of Biomolecular Structure and Dynamics, 39(9), 1–13. doi: 10.1080/07391102.2020.1764868.

Hartini, Y., Saputra, B., Wahono, B., Auw, Z., Indayani, F., Adelya, L., Namba, G., and Hariono, M., 2021. Biflavonoid as Potential 3-Chymotrypsin-Like Protease (3CLpro) Inhibitor of SARS-Coronavirus. Results in Chemistry, 3, 100087. doi: 10.1016/j.rechem.2020.100087

Hu, T., Liu, Y., Zhao, M., Zhuang, Q., Xu, L., and He, Q., 2020. A Comparison of COVID-19, SARS and MERS. PeerJ, 8, e9725. doi: 10.7717/peerj.9725.

Iheagwam, F. N., and Rotimi, S. O., 2020. Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants. Scientifica, 2020, 1878410. doi: 10.1155/2020/1878410.

Johnson, T. A., McLeod, M. J., and Holyoak, T., 2016. Utilization of Substrate Intrinsic Binding Energy for Conformational Change and Catalytic Function in Phosphoenolpyruvate Carboxykinase. Biochemistry, 55(3), 575–587. doi: 10.1021/acs.biochem.5b01215.

Kementerian Kesehatan Republik Indonesia. 2020. Situasi Terkini Perkembangan (COVID-19). Kemenkes, September.

Kotrechko, S., Timoshevskii, A., Kolyvoshko, E., Matviychuk, Y., and Stetsenko, N., 2017. Thermomechanical Stability of Carbyne-Based Nanodevices. Nanoscale Research Letters, 12(1), 327. doi: 10.1186/s11671-017-2099-4.

Kufareva, I., and Abagyan, R., 2012. Methods of Protein Structure Comparison. Methods in Molecular Biology, 857, 231–257. doi: 10.1007/978-1-61779-588-6_10.

Lotfi, M., Hamblin, M. R., and Rezaei, N., 2020. COVID-19: Transmission, Prevention, and Potential Therapeutic Opportunities. Clinica Chimica Acta, 508, 254–266. doi: 10.1016/j.cca.2020.05.044.

Macchiagodena, M., Pagliai, M., and Procacci, P., 2020. Inhibition of the Main Protease 3CLPro of the Coronavirus Disease 19 via Structure-Based Ligand Design and Molecular Modeling. In arXiv. 750, 137489.

Mahanthesh, M. ., Ranjith, D., Yaligar, R., Jyothi, R., Narappa, G., and Ravi, M., 2020. Swiss ADME Prediction of Phytochemicals Present in Butea monosperma (Lam.) Taub. Journal of Pharmacognosy and Phytochemistry, 9(3), 1799–1809.

Makeneni, S., Thieker, D. F., and Woods, R. J., 2018. Applying Pose Clustering and MD Simulations to Eliminate False Positives in Molecular Docking. Journal of Chemical Information and Modeling, 58(3), 605–614. doi: 10.1021/acs.jcim.7b00588.

Mohammad, T., Shamsi, A., Anwar, S., Umair, M., Hussain, A., Rehman, M. T., AlAjmi, M. F., Islam, A., and Hassan, M. I., 2020. Identification of High-Affinity Inhibitors Of SARS-CoV-2 Main Protease: Towards the Development of Effective COVID-19 therapy. Virus Research, 288, 198102. doi: 10.1016/j.virusres.2020.198102.

Mora, J. R., Marrero-Ponce, Y., García-Jacas, C. R., and Suarez Causado, A., 2020. Ensemble Models Based on QuBiLS-MAS Features and Shallow Learning for the Prediction of Drug-Induced Liver Toxicity: Improving Deep Learning and Traditional Approaches. Chemical Research in Toxicology, 33(7), 1855–1873. doi: 10.1021/acs.chemrestox.0c00030.

Osipiuk, J., Azizi, S. A., Dvorkin, S., Endres, M., Jedrzejczak, R., Jones, K. A., Kang, S., Kathayat, R. S., Kim, Y., Lisnyak, V. G., Maki, S. L., Nicolaescu, V., Taylor, C. A., Tesar, C., Zhang, Y. A., Zhou, Z., Randall, G., Michalska, K., Snyder, S. A., Dickinson, B. C., and Joachimiak, A., 2021. Structure of Papain-Like Protease from SARS-CoV-2 and its Complexes with Non-Covalent Inhibitors. Nature Communications, 12(1), 743. doi: 10.1038/s41467-021-21060-3.

Ramadhan, D. S. F., Fakih, T. M., and 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. doi: 10.33084/bjop.v3i4.1634.

Ronning, D. R., Iacopelli, N. M., and Mishra, V., 2010. Enzyme-Ligand Interactions that Drive Active Site Rearrangements in the Helicobacter Pylori 5′-Methylthioadenosine/S-Adenosylhomocysteine Nucleosidase. Protein Science, 19(12), 2498–2510. doi: 10.1002/pro.524.

Saied, A. S., Gebauer, J., Hammer, K., and Buerkert, A., 2008. Ziziphus spina-christi (L.) Willd.: A multipurpose fruit tree. Genetic Resources and Crop Evolution, 55(7), 929–937. doi: 10.1007/s10722-007-9299-1.

Shah, F. H., Lim, K. H., and Kim, S. J., 2021. Do Fever-Relieving Medicines Have Anti-COVID Activity: An Insight. Future Virology, 16(4). doi: 10.2217/fvl-2020-0398.

Singhal, T., 2020. A Review of Coronavirus Disease-2019 (COVID-19). Indian Journal of Pediatrics, 87(4), 281–286. doi: 10.1007/s12098-020-03263-6.

Su, H. xia, Yao, S., Zhao, W. feng, Li, M. jun, Liu, J., Shang, W. juan, Xie, H., Ke, C. qiang, Hu, H. chen, Gao, M. na, Yu, K. qian, Liu, H., Shen, J. shan, Tang, W., Zhang, L. ke, Xiao, G. fu, Ni, L., Wang, D. wen, Zuo, J. ping, Jiang, H. liang, Bai, F., Wu, Y., Ye, Y., and Xu, Y. Chun., 2020. Anti-SARS-CoV-2 Activities In Vitro of Shuanghuanglian Preparations and Bioactive Ingredients. Acta Pharmacologica Sinica, 41(9), 1167–1177. doi: 10.1038/s41401-020-0483-6.

Tahir ul Qamar, M., Alqahtani, S. M., Alamri, M. A., and Chen, L. L., 2020. Structural Basis of SARS-CoV-2 3CLpro and Anti-COVID-19 Drug Discovery from Medicinal Plants. Journal of Pharmaceutical Analysis, 10(4), 313–319. doi: 10.1016/j.jpha.2020.03.009.


  • There are currently no refbacks.