Abstract
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.
Highlights
In late 2019, a novel coronavirus termed SARS-CoV-2 emerged and spread around the world causing coronavirus disease 2019 (COVID-19)
When we compared the active sites of all analyzed proteases, they presented a remarkable degree of similarity
We evaluated the performance of the selected ensembles to distinguish between known actives and randomly selected decoy molecules based on the Area Under the Curve (AUC) of the Receiver Operator Characteristic (ROC) curves
Summary
In late 2019, a novel coronavirus termed SARS-CoV-2 emerged and spread around the world causing coronavirus disease 2019 (COVID-19). While pharmaceutical interventions primarily remained symptomatic, multiple clinical trials are investigating novel treatments, mainly based on drug repurposing [2,3]. The treatment of this infection with specific drugs constitutes an urgent and unmet medical need. Many computational and experimental efforts were directed toward targeting the main protease (Mpro ) of SARS-CoV-2 with small molecules leading to the discovery of multiple promising candidates [4,5,6,7,8,9]. A large share of drug attrition in clinical trials, especially regarding compound safety, can be traced back to low target specificity and off-target binding [10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
