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. 2021 May;39(8):2980-2992.
doi: 10.1080/07391102.2020.1758791. Epub 2020 Apr 26.

Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes

Ammar D Elmezayen  1 , Anas Al-Obaidi  1 , Alp Tegin Şahin  1 , Kemal Yelekçi  1
Affiliations

Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes

Ammar D Elmezayen et al. J Biomol Struct Dyn. 2021 May.

Abstract

In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.Communicated by Ramaswamy H. Sarma.

Keywords: ADMET; COVID-19; MD simulation; MM-PBSA; homology modeling; structure-based virtual screening.

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Figures

Figure 1.
Figure 1.
Workflow for identification of potential inhibitors against Mpro and TMPSS2 enzymes via structure-based virtual screening.
Figure 2.
Figure 2.
TMPRSS2 and human DESC1sequences alignment. Amino acids identity is shown in dark blue, and similarity is represented in light blue.
Figure 3.
Figure 3.
Structural alignment between the homology modeling of TMPRSS2 (target) and the crystal structure of DESC1 (template) showed an RMSD value of 0.40 Å.
Figure 4.
Figure 4.
Homology modeling (M0001) validation. (a) z-score plot shows model M0001 (black dot) within the range of native structure. (b) Local energy plot. (c) Ramachandran plot.
Figure 5.
Figure 5.
ERRAT scheme plot for the TMPRSS2 model. Red bars refer to the misfolded region at the 99% confidence level. Regions that exhibit misfolding at 95% confidence level are in yellow bars. Green bars specify the regions with the proper protein folding.
Figure 6.
Figure 6.
3D-interaction diagram for the top-ranked compounds. Mpro complexes: (a) Talampicillin, (b) Lurasidone, (c) ZINC000015988935, (d) ZINC000103558522. TMPRSS2 complexes: (e) Rubitecan, (f) Loprazolam, (g) ZINC000000702323, (h) ZINC000012481889.
Figure 7.
Figure 7.
2D-interaction diagram for the top-ranked Mpro-complexes: (a) Talampicillin, (b) Lurasidone, (c) ZINC000015988935, (d) ZINC000103558522.
Figure 8.
Figure 8.
2D-interaction diagram for the top-ranked TMPRSS2-complexes: (a) Rubitecan, (b) Loprazolam, (c) ZINC000000702323, (d) ZINC000012481889.
Figure 9.
Figure 9.
Electrostatic surface potential of top-ranked ligands. The electrostatic potential was predicted onto the surface of the protein of (a) Mpro_Talampicillin, (b) Mpro_ZINC000015988935 (c) TMPRSS2_Rubitecan and (d) TMPRSS2_ZINC000000702323. Positive and negative electrostatic charges are colored in blue and red, respectively.
Figure 10.
Figure 10.
50 ns-MD simulation RMSD plots of unbounded and bound enzymes. (a) Free Mpro in blue line, Mpro_Talampicillin in orange colored line and Mpro_ ZINC000015988935 complex in green line. (b) Free TMPRSS2 in pink line, TMPRSS2_Rubitecan complex in gray colored line and TMPRSS2_ ZINC000000702323 in yellow line.
Figure 11.
Figure 11.
RMSF profiles of free enzymes and complexes. (a) Free Mpro in blue line, Mpro_Talampicillin in orange colored line and Mpro_ZINC000015988935 complex in green line. (b) Free TMPRSS2 in pink line, TMPRSS2_Rubitecan complex in gray colored line and TMPRSS2_ ZINC000000702323 in yellow line.
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References

    1. Berry M., Fielding B. C., & Gamieldien J. (2015). Potential broad spectrum inhibitors of the Coronavirus 3CLpro: A virtual screening and structure-based drug design study. Viruses, 7(12), 6642–6660. 10.3390/v7122963 - DOI - PMC - PubMed
    1. Bhattacharya D., Nowotny J., Cao R., & Cheng J. (2016). 3Drefine: An interactive web server for efficient protein structure refinement. Nucleic Acids Research, 44(W1), W406–W409. 10.1093/nar/gkw336 - DOI - PMC - PubMed
    1. Boonstra S., Onck P. R., & Van Der Giessen E. (2016). CHARMM TIP3P Water Model Suppresses Peptide Folding by Solvating the Unfolded State. The Journal of Physical Chemistry B, 120(15), 3692–3698. 10.1021/acs.jpcb.6b01316 - DOI - PubMed
    1. Böttcher E., Matrosovich T., Beyerle M., Klenk H.-D., Garten W., & Matrosovich M. (2006). Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. Journal of Virology, 80(19), 9896–9898. 10.1128/JVI.01118-06 - DOI - PMC - PubMed
    1. Clark B. G., Jue S. G., Dawson G. W., & Ward A. (1986). Loprazolam: A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia. Drugs, 31(6), 500–516. doi.org/ - PubMed