Sains Malaysiana 53(5)(2024): 983-994

http://doi.org/10.17576/jsm-2024-5305-01

Unlocking Therapeutic Potential: Identifying Small Molecule Inhibitors for SARS-COV-2 Variants' Main Protease (M^PRO) Through Molecular Docking Analysis

(Membuka Kunci Potensi Terapeutik: Mengenal Pasti Perencatan Molekul Kecil untuk Protease Utama (M^PRO) Varian SARS-COV-2 Melalui Analisis Dok Molekul)

CHONG YIE WOON^1,2& NURUL IZZA ISMAIL^1,*

¹School of Biological Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia

²BiologicalDepartment of Chemistry, University of California Riverside, CA, USA

Diserahkan: 3 November 2023/Diterima: 8 April 2024

AbstraCT

Even with existing emergency drugs, the development of safer and more effective drugs for the treatment of COVID-19 still needs to continue. Virtual screening through a molecular docking approach is a powerful way to discover potential compounds for new drug discovery. In this study, we targeted SARS-CoV-2 wild-type major protease (M^Pro), beta, lambda and omicron variants, to conduct a virtual screening with a selection of 100 ligands from the PubChem database using AutoDock Vina software. Among the inhibitors that have been identified are ten compounds consisting of ergotamine, 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide], remetinostat, benzamidine, argifin, irinotecan, dihydroergotamine, telmisartan, bromocriptine, and cilengitide, which exhibited the highest binding affinity. Interaction analysis through BIOVIA Discovery Studio showed the binding and interaction modes between these inhibitors and M^Pro residues of the variant. This mainly refers to 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide] and remetinostat which consistently exhibit strong interactions with M^Pro variants. This research provides promising leads for the development of potential COVID-19 therapeutics. In summary, targeting conserved M^Pro with small molecule inhibitors provides a solid foundation for combating SARS-CoV-2 and its variants, holding promise for effective COVID-19 mitigation.

Keywords: COVID-19; molecular docking; M^Pro; remetinostat; 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide]

Abstrak

Walaupun dengan ubat kecemasan yang sedia ada, pembangunan ubat yang lebih selamat dan berkesan untuk rawatan COVID-19 masih perlu diteruskan. Penyaringan maya melalui pendekatan dok molekul merupakan satu cara yang terbaik untuk penemuan sebatian yang berpotensi  bagi penemuan ubat baharu. Dalam kajian ini, kami menyasarkan protease utama (M^Pro) jenis liar SARS-CoV-2, beta, lambda dan varian omikron, untuk dijalankan saringan maya dengan pemilihan 100 ligan daripada pangkalan data PubChem menggunakan perisian AutoDock Vina. Antara perencat yang telah dikenal pasti adalah sepuluh sebatian terdiri daripada ergotamin, 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide], remetinostat, benzamidine, argifin, irinotecan, dihydroergotamine, telmisartan, bromocriptine dan cilengitide yang menunjukkan pertalian pengikatan tertinggi. Analisis interaksi melalui BIOVIA Discovery Studio mendedahkan mod pengikatan dan interaksi antara perencat ini serta sisa M^Pro bagi varian tersebut. Ini terutamanya merujuk kepada 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide] dan remetinostat yang secara tekalnya menunjukkan interaksi yang kuat dengan varian M^Pro. Penyelidikan ini memberikan petunjuk yang berpotensi untuk pembangunan terapeutik COVID-19. Ringkasnya, menyasarkan M^Pro yang dipelihara dengan perencat molekul kecil menyediakan asas yang kukuh untuk memerangi SARS-CoV-2 dan variannya, memegang janji untuk mitigasi COVID-19 yang berkesan.

Kata kunci: COVID-19; dok molekul; M^Pro; remetinostat; 2,5-Dibenzyloxy-3-hydroxyligand-hexanedioic acid bis-[(2-hydroxy-indan-1-YL)-amide]

RUJUKAN

Adedeji, A.O. & Sarafianos, S.G. 2014. Antiviral drugs specific for coronaviruses in preclinical development. Current Opinion in Virology 8: 45-53.

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.

Bosshard, H.R., Marti, D.N. & Jelesarov, I. 2004. Protein stabilization by salt bridges: Concepts, experimental approaches and clarification of some misunderstandings. Journal of Molecular Recognition 17(1): 1-16.

Brylinski, M. 2018. Aromatic interactions at the ligand–protein interface: Implications for the development of docking scoring functions. Chemical Biology & Drug Design 91(2): 380-390.

Bzówka, M., Mitusińska, K., Raczyńska, A., Samol, A., Tuszyński, J.A. & Góra, A. 2020. Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design. International Journal of Molecular Sciences 21(9): 3099.

Chia, C.B., Xu, W. & Shuyi Ng, P. 2022. A patent review on SARS coronavirus main protease (3CLpro) inhibitors. ChemMedChem 17(1): e202100576.

Duarte, M., Pelorosso, F., Nicolosi, L.N., Salgado, M.V., Vetulli, H., Aquieri, A., Azzato, F., Castro, M., Coyle, J., Davolos, I., Fernandez Criado, I., Gregori, R., Mastrodonato, P., Rubio, M.C., Sarquis, S., Wahlmann, F. & Rothlin, R.P. 2021. Telmisartan for treatment of COVID-19 patients: An open multicenter randomized clinical trial. EClinicalMedicine 37: 100962.

Flynn, J.M., Zvornicanin, S.N., Tsepal, T., Shaqra, A.M., Kurt Yilmaz, N., Jia, W., Moquin, S., Dovala, D., Schiffer, C.A. & Bolon, D.N.A. 2023. Contributions of hyperactive mutations in Mpro from SARS-CoV-2 to drug resistance. ACS Infectious Diseases 10(4): 1174-1184.

Gentile, F., Yaacoub, J.C., Gleave, J., Fernandez, M., Ton, A.T., Ban, F., Stern, A. & Cherkasov, A. 2022. Artificial intelligence–enabled virtual screening of ultra-large chemical libraries with deep docking. Nature Protocols 17(3): 672-697.

Govardhanagiri, S., Bethi, S. & Nagaraju, G.P. 2019. Small molecules and pancreatic cancer trials and troubles. In Breaking Tolerance to Pancreatic Cancer Unresponsiveness to Chemotherapy, edited by Nagaraju, G.P. London: Academic Press. pp. 117-131.

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.

Greasley, S.E., Noell, S., Plotnikova, O., Ferre, R., Liu, W., Bolanos, B., Fennell, K., Nicki, J., Craig, T., Zhu, Y., Stewart, A.E. & Steppan, C.M. 2022. Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. Journal of Biological Chemistry 298(6): 101972.

Gul, S., Ozcan, O., Asar, S., Okyar, A., Barıs, I. & Kavakli, I.H. 2021. In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials. Journal of Biomolecular Structure and Dynamics 39(17): 6772-6791.

Gurung, A.B., Ali, M.A., Lee, J., Farah, M.A. & Al-Anazi, K.M. 2020. In silico screening of FDA approved drugs reveals ergotamine and dihydroergotamine as potential coronavirus main protease enzyme inhibitors. Saudi Journal of Biological Sciences 27(10): 2674-2682.

Hakmi, M., Bouricha, E.M., Kandoussi, I., El Harti, J. & Ibrahimi, A. 2020. Repurposing of known anti-virals as potential inhibitors for SARS-CoV-2 main protease using molecular docking analysis. Bioinformation 16(4): 301-306.

Higueruelo, A.P., Schreyer, A., Bickerton, G.R.J., Pitt, W.R., Groom, C.R. & Blundell, T.L. 2009. Atomic interactions and profile of small molecules disrupting protein–protein interfaces: The TIMBAL database. Chemical Biology & Drug Design 74(5): 457-467.

Horowitz, S. & Trievel, R.C. 2012. Carbon-oxygen hydrogen bonding in biological structure and function. Journal of Biological Chemistry 287(50): 41576-41582.

Hosseini, M., Chen, W., Xiao, D. & Wang, C. 2021. Computational molecular docking and virtual screening revealed promising SARS-CoV-2 drugs. Precision Clinical Medicine 4(1): 1-16.

Huang, H., Zhang, G., Zhou, Y., Lin, C., Chen, S., Lin, Y., Mai, S. & Huang, Z. 2018. Reverse screening methods to search for the protein targets of chemopreventive compounds. Frontiers in Chemistry 6: 138.

Hung, Y.P., Lee, J.C., Chiu, C.W., Lee, C.C., Tsai, P.J., Hsu, I.L. & Ko, W.C. 2022. Oral Nirmatrelvir/Ritonavir therapy for COVID-19: The dawn in the dark? Antibiotics 11(2): 220.

Hwang, J., Dial, B. E., Li, P., Kozik, M. E., Smith, M. D., & Shimizu, K. D. (2015). How important are dispersion interactions to the strength of aromatic stacking interactions in solution? Chemical Science, 6(7), 4358-4364.

Khalifa, H.O. & Al Ramahi, Y.M. 2024. After the hurricane: Anti-COVID-19 drugs development, molecular mechanisms of action and future perspectives. International Journal of Molecular Sciences 25(2): 739.

Khan, S.L., Siddiqui, F.A., Jain, S.P. & Sonwane, G.M. 2021. Discovery of potential inhibitors of SARS-CoV-2 (COVID-19) main protease (Mpro) from Nigella sativa (black seed) by molecular docking study. Coronaviruses 2(3): 384-402.

Kneller, D.W., Phillips, G., O’Neill, H.M., Jedrzejczak, R., Stols, L., Langan, P., Joachimiak, A., Coates, L. & Kovalevsky, A. 2020. Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography. Nature Communications 11(1): 3202.

Lam, C. & Patel, P. 2023. Nirmatrelvir-Ritonavir. In StatPearls [Internet]. StatPearls Publishing.

Lee, J., Worrall, L.J., Vuckovic, M., Rosell, F.I., Gentile, F., Ton, A.T., Cavaney, N.A., Ban, F., Cherkasov, A., Paetzel, M. & Strynadka, N.C.J. 2020. Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site. Nature Communications 11: 5877.

Li, Z., Li, X., Huang, Y.Y., Wu, Y., Liu, R., Zhou, L., Lin, Y., Wu, D., Zhang, L., Liu, H., Xu, X., Yu, K., Zhang, Y., Cui, J., Zhan, C.G., Wang, X. & Luo, H.B. 2020. Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs. Proceedings of the National Academy of Sciences 117(44): 27381-27387.

Lovetrue, B. 2020. The AI-discovered aetiology of COVID-19 and rationale of the irinotecan+ etoposide combination therapy for critically ill COVID-19 patients. Medical Hypotheses 144: 110180.

Morse, J.S., Lalonde, T., Xu, S. & Liu, W.R. 2020. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019‐nCoV. Chembiochem. 21(5): 730-738.

Muppalaneni, N.B. & Rao, A.A. 2011. PDBToSDF: Create ligand structure files from PDB file. Bioinformation 6(10): 383.

Nader, D., Fletcher, N., Curley, G.F. & Kerrigan, S.W. 2021. SARS-CoV-2 uses major endothelial integrin αvβ3 to cause vascular dysregulation in-vitro during COVID-19. PLoS ONE 16(6): e0253347.

Nutho, B., Mahalapbutr, P., Hengphasatporn, K., Pattaranggoon, N.C., Simanon, N., Shigeta, Y., Hannongbua, S. & Rungrotmongkol, T. 2020. Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms. Biochemistry 59(18): 1769-1779.

Odhar, H.A., Ahjel, S.W., Albeer, A.A.M.A., Hashim, A.F., Rayshan, A.M. & Humadi, S.S. 2020. Molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus. Bioinformation 16(3): 236-244.

Ordog, R., Szabadka, Z. & Grolmusz, V. 2009. DECOMP: A PDB decomposition tool on the web. Bioinformation 3(10): 413-414.

Pang, X., Xu, W., Liu, Y., Li, H. & Chen, L. 2023. The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022. European Journal of Medicinal Chemistry 257: 115491.

Rothlin, R.P., Duarte, M., Pelorosso, F.G., Nicolosi, L., Salgado, M.V., Vetulli, H.M. & Spitzer, E. 2021. Angiotensin receptor blockers for COVID-19: Pathophysiological and pharmacological considerations about ongoing and future prospective clinical trials. Frontiers in Pharmacology 12: 603736.

Saluja, H., Mehanna, A., Panicucci, R. & Atef, E. 2016. Hydrogen bonding: Between strengthening the crystal packing and improving solubility of three haloperidol derivatives. Molecules 21(6): 719.

Santos-Filho, O.A., Eynde, J.J.V., Mayence, A. & Huang, T.L. 2020. Evaluation of aryl amidines/benzimidazoles as potential anti-COVID-19 agents: A computational study. https://doi.org/10.3390/ECMC2020-07288

Shah, B., Modi, P. & Sagar, S.R. 2020. In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life Sciences 252: 117652.

Steiner, T. 2002. The hydrogen bond in the solid state. Angewandte Chemie International Edition 41(1): 48-76.

Steiner, T. & Desiraju, G.R. 1998. Distinction between the weak hydrogen bond and the van der Waals interaction. Chemical Communications 8: 891-892.

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.

Vatansever, E.C., Yang, K.S., Drelich, A.K., Kratch, K.C., Cho, C.C., Kempaiah, K.R., Hsu, J.C., Mellott, D.M., Xu, S., Tseng, C-T.K. & Liu, W.R. 2021. Bepridil is potent against SARS-CoV-2 in vitro. Proceedings of the National Academy of Sciences 118(10): e2012201118.

Wade, R.C. & Goodford, P.J. 1989. The role of hydrogen-bonds in drug binding. Progress in Clinical and Biological Research 289: 433-444.

Xiang, R., Yu, Z., Wang, Y., Wang, L., Huo, S., Li, Y., Liang, R., Hao, Q., Ying, T., Gao, Y., Yu, F. & Jiang, S. 2022. Recent advances in developing small-molecule inhibitors against SARS-CoV-2. Acta Pharmaceutica Sinica B 12(4): 1591-1623.

Xie, N.Z., Du, Q.S., Li, J.X. & Huang, R.B. 2015. Exploring strong interactions in proteins with quantum chemistry and examples of their applications in drug design. PLoS ONE 10(9): e0137113.

Xiong, R., Zhang, L., Li, S., Sun, Y., Ding, M., Wang, Y., Zhao, Y., Wu, Y., Shang, W., Jiang, X., Shan, J., Shen, Z., Tong, Y., Xu, L., Chen, Y., Liu, Y., Zou, G., Lavillete, D., Zhao, Z., Wang, R., Zhu, L., Xiao, G., Lan, K., Li, H. & Xu, K. 2020. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein & Cell 11(10): 723-739.

Yuce, M., Cicek, E., Inan, T., Dag, A.B., Kurkcuoglu, O. & Sungur, F.A. 2021. Repurposing of FDA‐approved drugs against active site and potential allosteric drug‐binding sites of COVID‐19 main protease. Proteins: Structure, Function, and Bioinformatics 89(11): 1425-1441.

Yunta, M.J. 2017. It is important to compute intramolecular hydrogen bonding in drug design. Am. J. Model. Optim. 5(1): 24-57.

Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. & 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.

Zheng, J., Zhang, Y., Zhao, H., Liu, Y., Baird, D., Karim, M.A., Ghoussaini, M., Schwartzentruber, J., Dunham, I., Elsworth, B., Roberts, K., Compton, H., Miller-Molloy, F., Liu, X., Wang, L., Zhang, H., Smith, G.D. & Gaunt, T.R. 2020. Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity. eBioMedicine 81: 104112. https://doi.org/10.1016/j.ebiom.2022.104112

*Pengarang untuk surat-menyurat; email: nurul.ismail@usm.my