Next Article in Journal
Why Do Muse Stem Cells Present an Enduring Stress Capacity? Hints from a Comparative Proteome Analysis
Next Article in Special Issue
Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis
Previous Article in Journal
Lysines Acetylome and Methylome Profiling of H3 and H4 Histones in Trichostatin A—Treated Stem Cells
Previous Article in Special Issue
Human Milk Antibodies against S1 and S2 Subunits from SARS-CoV-2, HCoV-OC43, and HCoV-229E in Mothers with a Confirmed COVID-19 PCR, Viral SYMPTOMS, and Unexposed Mothers

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

Computational Pharmacy, Departement of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
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;
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
Show Figures

Figure 1

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.

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.

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.

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Back to TopTop