Homology modelling and molecular docking study of TMPRSS2 with small-molecule protease inhibitors to control SARS-CoV-2


  • Salha M Tawati School of Life Sciences, Glasgow University, Scotland, United Kingdom / Faculty of Pharmacy, University of Benghazi, Benghazi, Libya
  • Aisha A Alsfouk Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
  • Asma Alsarrah Faculty of Pharmacy, University of Benghazi, Benghazi, Libya / Washtenaw Community College, Ann Arbor, MI, United States




Due to the urgent need of drugs to control the COVID-19 pandemic, repositioning of already marketed drugs could be a fast and convenient option  to identify agents to aid in controlling and treating COVID-19. This work presented a computational work regarding homology modeling and molecular docking of repurposing drugs related to the SARS-CoV-2. We have created a homology model of the cell surface transmembrane protease serine 2 protein (TMPRSS2) in order to investigate and analyze the interactions of already known small-molecules. This study indicates the most active inhibitors, poceprevir, simeprevir and neoandrgrapholide, that can be used further to search for better TMPRSS2 inhibitors.  Moreover,  we analyzed  the most important atomistic connections between these compounds and the modeled protein pockets. This study will focus on TMPRSS2-targeted drugs by comparing the binding mode of approved and experimentally used TMRSS2 inhibitors with other agents with TMPRSS2 inhibitory activity and could potentially inhibit SARS-CoV-2 and therefore could lead to the identification of new agents for further clinical evaluation of SARS-CoV-2 and potential treatment of COVID-19.


COVID-19, SARS-Coronavirus 2, serine protease


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A Mittal, K Manjunath, R K Ranjan, S Kaushik, S Kumar, and V Verma. COVID-19 pandemic: Insights into structure, function, and hACE2 receptor recognition by SARS-CoV-2. PLoS Pathog, 16(8), 2020.

R Yan, Y Zhang, Y Li, L Xia, Y Guo, and Q Zhou. Structural basis for the recognition of SARS- CoV-2 by full-length human ACE2. Science, 367(6485):1444–1448, 2020.

M Hoffmann, H Hofmann-Winkler, J C Smith, N Krüger, L K Sørensen, O S Søgaard, and J B Hasselstrøm. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. bioRxiv. Accessed On: 05 August 2020.

M Hoffmann, H Kleine-Weber, S Schroeder, N Krüger, T Herrler, S Erichsen, T S Schier- gens, and G Herrler. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181(2):271–280, 2020.

V Monteil, H Kwon, P Prado, A Hagelkrüys, R A Wimmer, M Stahl, A Leopoldi, and E Garreta. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell, 181(4):905–913, 2020.

N Iwata-Yoshikawa, T Okamura, Y Shimizu, H Hasegawa, M Takeda, and N Nagata. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol, 93(6):1–15, 2019.

F Sielaff, E Böttcher-Friebertshäuser, D Meyer, S M Saupe, I M Volk, W Garten, and T Steinmetzer. Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT. Bioorganic Med Chem Lett [Internet], 21(16):4860–4864, 2011.

C Camacho, G Coulouris, V Avagyan, N Ma, J Papadopoulos, K Bealer, and T L Madden. BLAST+: architecture and applications. BMC Bioinformatics, 10:421–421, 2009.

A Waterhouse, M Bertoni, S Bienert, G Studer, G Tauriello, R Gumienny, F T Heer, De Beer, Tap Rempfer, C Bordoli, L Lepore, and R Schwede. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res, 46(W1):296–303, 2018.

Jarg Barbosa, J W Saldanha, and R C Garratt. Novel features of serine protease active sites and specificity pockets: sequence analysis and modelling studies of glutamate-specific endopeptidases and epidermolytic toxins. Protein Engineering, Design and Selection, 9(7):591–601, 1996.

C Wu, Y Liu, Y Yang, P Zhang, W Zhong, Y Wang, Q Wang, Y Xu, and M Li. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B, 10(5):766–88, 2020.

K D Sonawane, S S Barale, M J Dhanavade, S R Waghmare, N H Nadaf, S A Kamble, A A Mohammed, A M Makandar, P M Fandilolu, A S Dound, and N M Naik. Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modelling approach. Informatics in Medicine Unlocked, 24(8):100597–100597, 2020.

S Habtemariam, S F Nabavi, S Ghavami, C A Cismaru, I Berindan-Neagoe, and S M Nabavi. Possible use of the mucolytic drug bromhexine hydrochloride as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2. Pharmacol Res, 157:104853–104853, 2020.

R Cannalire, I Stefanelli, C Cerchia, A R Bec- cari, S Pelliccia, and V Summa. SARS-CoV- 2 Entry Inhibitors: Small Molecules and Pep- tides Targeting Virus or Host Cells. Int J Mol Sci, 21(16):1–27, 2020.

J H Shrimp, S C Kales, P E Sanderson, A Simeonov, M Shen, and M D Hall. An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19. ACS Pharma- col. Transl. Sci, 2020(5):997–1007.

Chunlong Ma, Michael Dominic Sacco, Brett Hurst, Julia Alma Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, and Bart Tarbet. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Research, 30(8):678–692, 2020.

H S Lo, Kpy Hui, H M Lai, K S Khan, S Kaur, J Huang, Z Li, and A Chan. Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir. ACS Cent Sci, 7(5):792–802, 2020.

V B Chen, W B Arendall, J J Headd, D A Keedy, R M Immormino, G J Kapral, L W Murray, J S Richardson, and D C Richardson. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr Sect D Biol Crystallogr, 66(1):12–21, 2010.

R A Laskowski, M W Macarthur, D S Moss, and J M Thornton. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr, 26(2):283–91, 1993.

W Tian, C Chen, X Lei, J Zhao, and J Liang. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Research, 46(W1):363– 367, 2018.

G M Morris, H Ruth, W Lindstrom, M F Sanner, R K Belew, D S Goodsell, and A J Olson. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem, 30(16):2785–91, 2009.

O Trott and A J Olson. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry, 31:455–461, 2010.

I Sánchez-Linares, H Pérez-Sánchez, J M Cecilia, and J M García. High-Throughput parallel blind Virtual Screening using Bindsurf. BMC Bioinformatics, 13(14), 2012.

S Salentin, S Schreiber, V J Haupt, M F Adasme, and M Schroeder. PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Research, 43(W1):443–450, 2015.

J Haas, A Barbato, D Behringer, G Studer, S Roth, M Bertoni, K Mostaguir, R Gumienny, and T Schwede. Continuous Automated Model Evaluation (CAMEO) complementing the critical assessment of structure prediction in CASP12. Protein, 86(5):387–398, 2018.



How to Cite

Salha M Tawati, Aisha A Alsfouk, & Asma Alsarrah. (2022). Homology modelling and molecular docking study of TMPRSS2 with small-molecule protease inhibitors to control SARS-CoV-2. International Journal of Research in Pharmaceutical Sciences, 13(2), 201–210. https://doi.org/10.26452/ijrps.v13i2.190



Original Articles