Potential inhibitors for targeting Mpro and Spike of SARS-CoV-2 based on sequence and structural pharmacology analysis

  • Chuanjun Shu Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211166, China
  • Xuan Huang Reproductive Medical Center, Jinling Hospital Affiliated to The Medical School of Nanjing University, Nanjing, 210002, China
  • Ting Huang Department of Pharmacy, Xuzhou Maternity and Child Health Care Hospital, Xuzhou, 221000, China
  • Li Chen Reproductive Medical Center, Jinling Hospital Affiliated to The Medical School of Nanjing University, Nanjing, 210002, China
  • Bing Yao Reproductive Medical Center, Jinling Hospital Affiliated to The Medical School of Nanjing University, Nanjing, 210002, China
  • Jianwei Zhou Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
  • Cheng Deng Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
Keywords: SARS-CoV-2, Mpro, Spike, Structural pharmacology analysis, New peptide inhibitor


The SARS-CoV-2 outbreak has spread rapidly and widely since December 2019, and the effective drugs are urgently needed. The two key proteins, Mpro and Spike, are attractive therapy targets for developing drugs against SARS-CoV-2 infection. In this study, we searched for the potential inhibitors targeting Mpro and Spike based on protein sequences and structural pharmacological analysis. We found that both Mpro and Spike of SARS-CoV-2 were homologous with bat SARS-like-CoV. SARS-CoV-2 Mpro showed high conservation (sequence similarities >99%), and the existing few point mutants in different patients from diverse cities suggested that SARS-CoV-2 probably underwent adaptive evolution when the virus infection transmitted from Wuhan patients to other non-Wuhan patients. Moreover, some inhibitors for SARS-CoV Mpro could probably inhibit the activity of SARS-CoV-2 Mpro, because they do not target conserved mutated sites of SARS-CoV-2 Mpro, such as SDJ, ACE-THR-VAL-ALC-HIS-H, B4Z inhibitor, Beclabuvir, Saquinavir, and Lopinavir. In contrast, Spike of SARS-CoV-2 had more mutations and some mutant sites were distributed in the interaction domain between Spike and ACE2. A new peptide FRKSNLKPFERDISTEIYQAGSTPC, based on interactions between Spike and ACE2, could be a potential drug to treat SARS-CoV-2 patients. In summary, our study provided potential new inhibitors for targeting Mpro and Spike in SARS-CoV-2 virus-infected patients based on sequence and structural pharmacology analysis.


Download data is not yet available.


Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.

Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J-x, et al. Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv. 2020:2020.02.06.20020974.

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020 Feb 7. [Epub ahead of print]

Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7(1):4.

Zhang Z, Li X, Zhang W, Shi ZL, Zheng Z, Wang T. Clinical features and treatment of 2019-nCov pneumonia patients in Wuhan: report of a couple cases. Virol Sin. 2020 Feb 7. [Epub ahead of print]

Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 2020 Mar 11;27(3):325-328.

Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW, Huang Y, et al. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol. 2005 Jan; 79(2): 884-895.

Shimamoto Y, Hattori Y, Kobayashi K, Teruya K, Sanjoh A, Nakagawa A, et al. Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors. Bioorg Med Chem. 2015 Feb 15; 23(4):876-90.

Wong, K. S. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem. 2004 Jan 30;279(5):3197-201.

Kirchdoerfer RN, Cottrell CA, Wang N, Pallesen J, Yassine HM, Turner HL, et al. Pre-fusion structure of a human coronavirus spike protein. Nature. 2016 Mar 3;531(7592):118-21.

Wang S, Guo F, Liu K, Wang H, Rao S, Yang P, et al. Endocytosis of the receptor-binding domain of SARS-CoV spike protein together with virus receptor ACE2. Virus Res. 2008 Sep;136(1-2):8-15.

Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31.

Liu W, Morse JS, Lalonde T, Xu S. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembiochem. 2020 Mar 2;21(5):730-738.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.

Helge-Friedrich T. Analysis for free: Comparing programs for sequence analysis. Brief Bioinform. 2004 Mar;5(1):82-7.

Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool (BLAST). J Mol Biol. 1990 Oct 5;215(3):403-10.

Sussman JL, Lin D, Jiang J, Manning NO, Prilusky J, Ritter O, et al. Protein data bank (PDB): database of three-dimensional structural information of biological macromolecules&nbsp. Acta Crystallographica. 2010;54(6-1):1078-84.

Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome Res. 2004 Jun; 14(6):1188–1190.

Lewis PO, Kumar S, Tamura K, Nei M. MEGA: molecular evolutionary genetics analysis, version 1.02. Systematic Biology. 1995;44(4).

Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc. 2010 Apr;5(4):725–738.

Garg VK, Avashthi H, Tiwari A. MFPPI – multi FASTA ProtParam interface. Bioinformation. 2016;12(2): 4–77.

Dolinsky TJ, Nielsen JE, Andrew MJ, Baker NA. PDB2PQR: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res. 2004 Jul 1; 32(Web Server issue):W665–W667.

Rohl CA, Strauss CE, Misura KM, Baker D. Protein structure prediction using Rosetta. Method Enzymol. 2004;383:66-93.

Gao YD, Huang JF. An extension strategy of Discovery Studio 2.0 for non-bonded interaction energy automatic calculation at the residue level. Dongwuxue Yanjiu. 2011 Jun;32(3):262-6. [Article in Chinese]

Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013 Jun;45(6):580–585.

Ordog R. PyDeT, a PyMOL plug-in for visualizing geometric concepts around proteins. Bioinformation. 2008;2(8):346–347.

How to Cite
ShuC., HuangX., HuangT., ChenL., YaoB., ZhouJ., & DengC. (2020). Potential inhibitors for targeting Mpro and Spike of SARS-CoV-2 based on sequence and structural pharmacology analysis. STEMedicine, 1(2), e41. https://doi.org/10.37175/stemedicine.v1i2.41
Research articles