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Article

Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2

1
Computational Pharmacy, Departement of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
2
Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Cristina Belizna, Jan Willem Cohen Tervaert, Yehuda Shoenfeld and Alexander Makatsariya
Int. J. Mol. Sci. 2021, 22(4), 2065; https://doi.org/10.3390/ijms22042065
Received: 4 January 2021 / Revised: 8 February 2021 / Accepted: 11 February 2021 / Published: 19 February 2021
(This article belongs to the Special Issue COVID-19 and Molecular Studies in Biology and Chemistry)
The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (Mpro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 Mpro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV Mpro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 Mpro inhibitors, as we report it, was not previously conducted. View Full-Text
Keywords: coronavirus; SARS; protease; selectivity; structure-based design coronavirus; SARS; protease; selectivity; structure-based design
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MDPI and ACS Style

Fischer, A.; Sellner, M.; Mitusińska, K.; Bzówka, M.; Lill, M.A.; Góra, A.; Smieško, M. Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2. Int. J. Mol. Sci. 2021, 22, 2065. https://doi.org/10.3390/ijms22042065

AMA Style

Fischer A, Sellner M, Mitusińska K, Bzówka M, Lill MA, Góra A, Smieško M. Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2. International Journal of Molecular Sciences. 2021; 22(4):2065. https://doi.org/10.3390/ijms22042065

Chicago/Turabian Style

Fischer, André, Manuel Sellner, Karolina Mitusińska, Maria Bzówka, Markus A. Lill, Artur Góra, and Martin Smieško. 2021. "Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2" International Journal of Molecular Sciences 22, no. 4: 2065. https://doi.org/10.3390/ijms22042065

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