Sains Malaysiana 50(5)(2021): 1473-1483

http://doi.org/10.17576/jsm-2021-5005-26

Molecular Docking Unveils Prospective Inhibitors for the SARS-COV-2 Main Protease

(Mengedok Molekul Mendedahkan Prospektif Perencat untuk Protease Utama SARS-COV-2)

FAWAD AHMAD¹, SAIMA IKRAM¹, JAMSHAID AHMAD¹*, IRSHAD UR REHMAN¹, SAEED ULLAH KHATTAK¹, SADIA BUTT² & MARYAM MUSHTAQ³

¹Centre of Biotechnology & Microbiology, University of Peshawar, Peshawar, Pakistan

²Shaheed Benazir Bhutto Women University, Peshawar, Pakistan

³Northwest General Hospital & Research Center, Peshawar, Pakistan

Diserahkan: 16 Januari 2021/Diterima: 17 Mac 2021

ABSTRACT

The recent emergence of a novel coronavirus strain (SARS-CoV-2) has stimulated global efforts to identify potential drugs that target proteins expressed by this novel coronavirus. Among these, the main protease of SARS-CoV-2 (3CL-protease (3CL^Pro), also known as (M^Pro) is one of the best choices for the scientists to target. 3CL^Pro is involved in the processing of polyproteins into mature non-structural viral proteins. An X-ray crystallographic structure (PDB ID 6LU7) of this protein was obtained from the PDB database. ChemDiv libraries of ~80,000 antiviral and ~13,000 coronavirus-targeting molecules were screened against the 3D structure of 3CL^Pro of SARS-CoV-2. We have identified a panel of molecules that showed an activity and potentially block the active site of the SARS-CoV-2 main protease. These molecules can be investigated further to develop effective virus-inhibiting molecules to treat this highly distressing disease, causing extreme unrest across the globe.

Keywords: Antivirals; coronavirus library; COVID-19; SARS-CoV-2; virtual screening

ABSTRAK

Kemunculan strain koronavirus baru-baru ini (SARS-CoV-2) telah mendorong usaha global untuk mengenal pasti ubat berpotensi yang mensasarkan protein yang diekspres oleh novel koronavirus ini. Antaranya, protease utama SARS-CoV-2 (3CL-protease (3CL^Pro), juga dikenali sebagai (M^Pro) adalah salah satu pilihan terbaik untuk disasarkan oleh para saintis. 3CL^Pro terlibat dalam pemprosesan poliprotein kepada virus protein matang tak-berstruktur. Struktur kristalografi sinar-X (PDB ID 6LU7) protein ini diperoleh dari pangkalan data PDB. Perpustakaan ChemDiv dengan ~80,000 antivirus dan ~13,000 molekul penyasaran koronavirus disaring terhadap struktur 3D 3CL^Pro SARS-CoV -2. Kami telah mengenal pasti panel molekul yang menunjukkan aktiviti dan berpotensi menyekat tapak aktif protease utama SARS-CoV-2. Molekul ini boleh dikaji lebih lanjut untuk mengembangkan molekul perencatan-virus yang berkesan untuk merawat penyakit yang menyebabkan keresahan melampau di seluruh dunia ini.

Kata kunci: Antivirus; COVID-19; perpustakaan koronavirus; saringan maya; SARS-CoV-2

RUJUKAN

Bas, D.C., Rogers, D.M. & Jensen, J.H. 2008. Very fast prediction and rationalization of pKa values for protein-ligand complexes. Proteins: Structure, Function, and Bioinformatics 73(3): 765-783.

Cui, J., Li, F. & Shi, Z.L. 2019. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 17(3): 181-192.

Durdagi, S., Aksoydan, B., Dogan, B., Sahin, K. & Shahraki, A. 2020. Screening of clinically approved and investigation drugs as potential inhibitors of COVID-19 main protease: A virtual drug repurposing study. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12032712.v1.

Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shelley, M., Perry, J.K., Shaw, D.E., Francis, P. & Shenkin, P.S. 2004. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry 47(7): 1739-1749.

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J. & Cao, B. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395(10223): 497-506.

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 COVID-19 virus and discovery of its inhibitors. Nature 582(7811): 289-293.

Li, F. 2016. Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3(1): 237-261.

Ren, L.L., Wang, Y.M., Wu, Z.Q. & Wang, J.W. 2020. Identification of a novel coronavirus causing severe pneumonia in human: A descriptive study. Chin. Med. J. (Engl) 133(9): 1015-1024.

Sastry, G.M., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. 2013. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design 27(3): 221-234.

Shelley, J.C., Cholleti, A., Frye, L.L., Greenwood, J.R., Timlin, M.R. & Uchimaya, M. 2007. Epik: A software program for pK a prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design 21(12): 681-691.

Shivakumar, D., Williams, J., Wu, Y., Damm, W., Shelley, J. & Sherman, W. 2010. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. Journal of Chemical Theory and Computation 6(5): 1509-1519.

Tang, Q., Song, Y., Shi, M., Cheng, Y., Zhang, W. & Xia, X.Q. 2015. Inferring the hosts of coronavirus using dual statistical models based on nucleotide composition. Sci. Rep. 5: 17155.

Thayil, S.M. & Thyagarajan, S. 2016. PA-9: A flavonoid extracted from Plectranthus amboinicus inhibits HIV-1 protease. International Journal of Pharmacognosy and Phytochemical Research 8(6): 1020-1024.

Wang, Z., Yang, B., Li, Q., Wen, L. & Zhang, R. 2020. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin. Infect. Dis. 71(15): 769-777.

Wu, D., Wu, T., Liu, Q. & Yang, Z. 2020a. The SARS-CoV-2 outbreak: What we know. Int. J. Infect Dis. 94: 44-48.

Wu, F., Zhao, Su., Yu, B., Chen, Y-M., Wang, W., Song, Z-G., Hu, Y., Tao, Z-W., Tian, J-H., Pei, Y-Y., Yuan, M-L., Zhang, Y-L, Dai, F-H., Liu, Y., Wang, Q-M., Zheng, J-J., Xu, L., Holmes, E.C. & Zhang, Y-Z. 2020b. A new coronavirus associated with human respiratory disease in China. Nature 579(7798): 265-269.

Wu, A., Peng, Y., Huang, B., Ding, X., Wang, X., Niu, P., Meng, J., Zhu, Z., Zhang, Z., Wang, J., Sheng, J., Quan, L., Xia, Z., Tan, W., Cheng, G. & Jiang, T. 2020c. Genome composition and divergence of the novel coronavirus (2019-nCoV) Originating in China. Cell Host Microbe 27(3): 325-328.

Zakaryan, H., Arabyan, E., Oo, A. & Zandi, K. 2017. Flavonoids: Promising natural compounds against viral infections. Archives of Virology 162(9): 2539-2551.

Zhou, P., Yang, X-L., Wang, X-G., Hu, B., Zhang, L., Zhang, W., Si, H-R., Zhu, Y., Li, B., Huang, C-L., Chen, H-D., Chen, J., Luo, Y., Guo, H., Jiang, R-D., Liu, M-Q., Chen, Y., Shen, X-R., Wang, X., Zheng, X-S., Zhao, K., Chen, Q-J., Deng, F., Liu, L-L., Yan, B., Zhan, F-X., Wang, Y-Y., Xiao, G-F. & Shi, Z-L. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798): 270-273.

*Pengarang untuk surat-menyurat; email: jamshaidbiotech@yahoo.com