Evaluation of the efficacy of available plant compounds as SARS-CoV-2 main protease inhibitors

Shahriarpour, Hamed; Naderi-Manesh, Hossein; Arab, Shahriar; Dehghanbanadaki, Najmeh

Evaluation of the efficacy of available plant compounds as SARS-CoV-2 main protease inhibitors

Document Type : Original Research

Authors

Hamed Shahriarpour

Hossein Naderi-Manesh

Shahriar Arab

Najmeh Dehghanbanadaki

Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

Abstract

The COVID-19 pandemic has created a global health crisis, and developing effective treatments is essential to prevent the spread of the disease and save millions of lives. One of the key proteins involved in the replication cycle of SARS-CoV-2, the virus that causes COVID-19, is the main protease enzyme, 3CL^pro. Due to its high importance, this enzyme is the subject of molecular, structural, and clinical investigations, and efforts have been made to develop drugs that can inhibit its activity. One such drug is the chemical compound N3, which has been found to have a high inhibitory effect against 3CL^pro. However, traditional medicine perspectives on this issue have been less explored. In this research, molecular docking interaction simulation and all-atom molecular dynamics (MD) simulation were conducted to study the potential inhibitory capability of generally available 21 plant-extracted compounds against the 3CL^pro enzyme. Three compounds with the highest inhibition probability were selected from the molecular docking results and subjected to 100 ns of MD simulation to investigate their stability and structural-dynamic-energetic features. Beside the complexes stability, the results from the simulation demonstrated that, all our selected three compounds induce N3 comparable structural-dynamics characteristics to 3CL^pro and, therefore, are expected to have a similar inhibitory ability against this enzyme. Compound number 5 was found to have the most favorable binding energy and was proposed as the best plant substitute for N3. The results from this research can be directly used to design experimental research for 3CLpro enzyme inhibition, saving the time-financial cost.

Keywords

SARS-CoV-2

main protease

Inhibitor

molecular docking

Molecular dynamics simulation

Subjects

Bioinformatics

[1] Chakraborty, I., & Maity, P. (2020). COVID-19 outbreak: Migration, effects on society, global environment and prevention. Science of the total environment, 728, 138882.
[2] Covid, W. (19). Coronavirus pandemic.
[3] Pal, M., Berhanu, G., Desalegn, C., & Kandi, V. (2020). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): an update. Cureus, 12(3).
[4] Dehelean, C. A., Lazureanu, V., Coricovac, D., Mioc, M., Oancea, R., Marcovici, I., ... & Cretu, O. (2020). SARS-CoV-2: repurposed drugs and novel therapeutic approaches—insights into chemical structure—biological activity and toxicological screening. Journal of clinical medicine, 9(7), 2084.
[5] Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., ... & Lane, H. C. (2020). Remdesivir for the treatment of Covid-19—preliminary report. New England Journal of Medicine, 383(19), 1813-1836.
[6] Cavalcanti, A. B., Zampieri, F. G., Rosa, R. G., Azevedo, L. C., Veiga, V. C., Avezum, A., ... & Berwanger, O. (2020). Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. New England Journal of Medicine, 383(21), 2041-2052.
[7] Horby, P., Lim, W. S., Emberson, J., Mafham, M., Bell, J., Linsell, L., ... & Landray, M. J. (2020). Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. 2020; 2020.06. 22.20137273. Publisher Full Text.
[8] Aygün, İ., Kaya, M., & Alhajj, R. (2020). Identifying side effects of commonly used drugs in the treatment of Covid 19. Scientific reports, 10(1), 21508.
[9] Kumari, M., Lu, R. M., Li, M. C., Huang, J. L., Hsu, F. F., Ko, S. H., ... & Wu, H. C. (2022). A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies. Journal of biomedical science, 29(1), 68.
[10] Yu, W., & MacKerell, A. D. (2017). Computer-aided drug design methods. Antibiotics: methods and protocols, 85-106.
[11] Lin, Y. (2022). Review of Modern Computer-aided Drug Design Methods. International Journal of Biology and Life Sciences, 1(1), 47-50.
[12] Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R., & Hilgenfeld, R. (2003). Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science, 300(5626), 1763-1767.
[13] Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., ... & Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.
[14] Chakraborty, C., Bhattacharya, M., Mallick, B., Sharma, A. R., Lee, S. S., & Agoramoorthy, G. (2021). SARS-CoV-2 protein drug targets landscape: a potential pharmacological insight view for the new drug development. Expert review of clinical pharmacology, 14(2), 225-237.
[15] Rohaim, M. A., El Naggar, R. F., Clayton, E., & Munir, M. (2021). Structural and functional insights into non-structural proteins of coronaviruses. Microbial pathogenesis, 150, 104641.
[16] Lichimo, K. (2022). 3CLpro: The discovery of host cell substrates and its relevance as a drug target for SARS-CoV-2 variants of concern. Undergraduate Journal of Experimental Microbiology and Immunology, 6.
[17] Razali, R., Asis, H., & Budiman, C. (2021). Structure-function characteristics of SARS-CoV-2 proteases and their potential inhibitors from microbial sources. Microorganisms, 9(12), 2481.
[18] ul Qamar, M. T., Alqahtani, S. M., Alamri, M. A., & 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.
[19] 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.
[20] Turlington, M., Chun, A., Tomar, S., Eggler, A., Grum-Tokars, V., Jacobs, J., ... & Stauffer, S. R. (2013). Discovery of N-(benzo [1, 2, 3] triazol-1-yl)-N-(benzyl) acetamido) phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorganic & medicinal chemistry letters, 23(22), 6172-6177.
[21] Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., & Sauerhering, L. & Hilgenfeld, R.(2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), 409-412.
[22] Harnkit, N., Khongsonthi, T., Masuwan, N., Prasartkul, P., Noikaew, T., & Chumnanpuen, P. (2022). Virtual Screening for SARS-CoV-2 Main Protease Inhibitory Peptides from the Putative Hydrolyzed Peptidome of Rice Bran. Antibiotics, 11(10), 1318.
[23] Hernández González, J. E., Eberle, R. J., Willbold, D., & Coronado, M. A. (2022). A computer-aided approach for the discovery of D-peptides as inhibitors of SARS-CoV-2 main protease. Frontiers in molecular biosciences, 8, 816166.
[24] Gutierrez-Villagomez, J. M., Campos-García, T., Molina-Torres, J., López, M. G., & Vázquez-Martínez, J. (2020). Alkamides and piperamides as potential antivirals against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The journal of physical chemistry letters, 11(19), 8008-8016.
[25] Antonopoulou, I., Sapountzaki, E., Rova, U., & Christakopoulos, P. (2022). Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds. Computational and Structural Biotechnology Journal, 20, 1306-1344.
[26] Bahun, M., Jukić, M., Oblak, D., Kranjc, L., Bajc, G., Butala, M., ... & Ulrih, N. P. (2022). Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols. Food chemistry, 373, 131594.
[27] Santana, K., Do Nascimento, L. D., Lima e Lima, A., Damasceno, V., Nahum, C., Braga, R. C., & Lameira, J. (2021). Applications of virtual screening in bioprospecting: facts, shifts, and perspectives to explore the chemo-structural diversity of natural products. Frontiers in Chemistry, 9, 662688.
[28] Gupta, S., Singh, A. K., Kushwaha, P. P., Prajapati, K. S., Shuaib, M., Senapati, S., & Kumar, S. (2021). Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies. Journal of Biomolecular Structure and Dynamics, 39(12), 4334-4345.
[29] 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 Mpro enzyme through in silico approach. Life sciences, 255, 117831.
[30] Jukič, M., Janežič, D., & Bren, U. (2021). Potential novel thioether-amide or guanidine-linker class of sars-cov-2 virus rna-dependent rna polymerase inhibitors identified by high-throughput virtual screening coupled to free-energy calculations. International Journal of Molecular Sciences, 22(20), 11143.
[31] Jiménez-Avalos, G., Vargas-Ruiz, A. P., Delgado-Pease, N. E., Olivos-Ramirez, G. E., Sheen, P., Fernández-Díaz, M., ... & Zimic, M. (2021). Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO. Scientific Reports, 11(1), 15452.
[32] Khamto, N., Utama, K., Tateing, S., Sangthong, P., Rithchumpon, P., Cheechana, N., ... & Meepowpan, P. (2023). Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CLPro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity. Journal of Chemical Information and Modeling, 63(7), 2104-2121.
[33] Newman, D. J., & Cragg, G. M. (2007). Natural products as sources of new drugs over the last 25 years. Journal of natural products, 70(3), 461-477.
[34] Jo, S., Kim, S., Shin, D. H., & Kim, M. S. (2020). Inhibition of SARS-CoV 3CL protease by flavonoids. Journal of enzyme inhibition and medicinal chemistry, 35(1), 145-151.
[35] Kolarič, A., Jukič, M., & Bren, U. (2022). Novel small-molecule inhibitors of the SARS-CoV-2 spike protein binding to neuropilin 1. Pharmaceuticals, 15(2), 165.
[36] Amporndanai, K., Meng, X., Shang, W., Jin, Z., Rogers, M., Zhao, Y., ... & Samar Hasnain, S. (2021). Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. Nature communications, 12(1), 3061.
[37] Jin, Z., Zhao, Y., Sun, Y., Zhang, B., Wang, H., Wu, Y., ... & Rao, Z. (2020). Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur. Nature structural & molecular biology, 27(6), 529-532.
[38] Ramos‐Guzmán, C. A., Ruiz‐Pernía, J. J., & Tuñón, I. (2021). Inhibition mechanism of SARS‐CoV‐2 main protease with ketone‐based inhibitors unveiled by multiscale simulations: insights for improved designs. Angewandte Chemie International Edition, 60(49), 25933-25941.
[39] Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., ... & Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.
[40] Kumar, A., Rai, A., Khan, M. S., Kumar, A., Haque, Z. U., Fazil, M., & Rabbani, G. (2022). Role of herbal medicines in the management of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials. Journal of traditional and complementary medicine, 12(1), 100-113.
[41] Zrig, A. (2022). The effect of phytocompounds of medicinal plants on coronavirus (2019-NCOV) infection. Pharmaceutical chemistry journal, 55(10), 1080-1084.
[42] Süntar, I. (2020). Importance of ethnopharmacological studies in drug discovery: role of medicinal plants. Phytochemistry Reviews, 19(5), 1199-1209.
[43] Hossain, R., Sarkar, C., Hassan, S. M. H., Khan, R. A., Arman, M., Ray, P., ... & Calina, D. (2022). In silico screening of natural products as potential inhibitors of SARS-CoV-2 using molecular docking simulation. Chinese journal of integrative medicine, 28(3), 249-256.
[44] Ghosh, R., Chakraborty, A., Biswas, A., & Chowdhuri, S. (2021). Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors–an in silico docking and molecular dynamics simulation study. Journal of Biomolecular Structure and Dynamics, 39(12), 4362-4374.
[45] Su, H., Yao, S., Zhao, W., Li, M., Liu, J., Shang, W., ... & Xu, Y. (2020). Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro. BioRxiv, 2020-04.
[46] Listiyani, P., Kharisma, V. D., Ansori, A. N. M., Widyananda, M. H., Probojati, R. T., Murtadlo, A. A. A., ... & Zainul, R. (2022). In silico phytochemical compounds screening of Allium sativum targeting the Mpro of SARS-CoV-2. Pharmacognosy Journal, 14(3).
[47] Mlozi, S. H. (2022). The role of natural products from medicinal plants against COVID-19: traditional medicine practice in Tanzania. Heliyon, 8(6).
[48] Schmid, N., Eichenberger, A. P., Choutko, A., Riniker, S., Winger, M., Mark, A. E., & Van Gunsteren, W. F. (2011). Definition and testing of the GROMOS force-field versions 54A7 and 54B7. European biophysics journal, 40, 843-856.
[49] Meza, J. C. (2010). Steepest descent. Wiley Interdisciplinary Reviews: Computational Statistics, 2(6), 719-722.
[50] Bornot, A., Etchebest, C., & De Brevern, A. G. (2011). Predicting protein flexibility through the prediction of local structures. Proteins: Structure, Function, and Bioinformatics, 79(3), 839-852.
[51] Burgoyne, N. J., & Jackson, R. M. (2006). Predicting protein interaction sites: binding hot-spots in protein–protein and protein–ligand interfaces. Bioinformatics, 22(11), 1335-1342.
[52] Harnkit, N., Khongsonthi, T., Masuwan, N., Prasartkul, P., Noikaew, T., & Chumnanpuen, P. (2022). Virtual Screening for SARS-CoV-2 Main Protease Inhibitory Peptides from the Putative Hydrolyzed Peptidome of Rice Bran. Antibiotics, 11(10), 1318.
[53] Lau, J. L., & Dunn, M. K. (2018). Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorganic & medicinal chemistry, 26(10), 2700-2707.
[54] Al Musaimi, O., Lombardi, L., Williams, D. R., & Albericio, F. (2022). Strategies for Improving Peptide Stability and Delivery. Pharmaceuticals, 15(10), 1283.
[55] Mahlapuu, M., Björn, C., & Ekblom, J. (2020). Antimicrobial peptides as therapeutic agents: Opportunities and challenges. Critical reviews in biotechnology, 40(7), 978-992.
[56] S. Ketabchi and M. Papari Moghadamfard. (2021) Medicinal Plants Effective in the Prevention and Control of Coronaviruses. Complement. Med. J., vol. 10, no. 4, pp. 296–307.
[57] Zrieq, R., Ahmad, I., Snoussi, M., Noumi, E., Iriti, M., Algahtani, F. D., ... & Kadri, A. (2021). Tomatidine and patchouli alcohol as inhibitors of SARS-CoV-2 enzymes (3CLpro, PLpro and NSP15) by molecular docking and molecular dynamics simulations. International Journal of Molecular Sciences, 22(19), 10693.