Version 1
: Received: 8 April 2020 / Approved: 9 April 2020 / Online: 9 April 2020 (14:59:37 CEST)
Version 2
: Received: 30 May 2020 / Approved: 1 June 2020 / Online: 1 June 2020 (02:42:54 CEST)
How to cite:
Olubiyi, O.O.; Olagunju, M.; Keutmann, M.; Loschwitz, J.; Strodel, B. High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2. Preprints2020, 2020040161. https://doi.org/10.20944/preprints202004.0161.v2
Olubiyi, O.O.; Olagunju, M.; Keutmann, M.; Loschwitz, J.; Strodel, B. High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2. Preprints 2020, 2020040161. https://doi.org/10.20944/preprints202004.0161.v2
Olubiyi, O.O.; Olagunju, M.; Keutmann, M.; Loschwitz, J.; Strodel, B. High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2. Preprints2020, 2020040161. https://doi.org/10.20944/preprints202004.0161.v2
APA Style
Olubiyi, O.O., Olagunju, M., Keutmann, M., Loschwitz, J., & Strodel, B. (2020). High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2. Preprints. https://doi.org/10.20944/preprints202004.0161.v2
Chicago/Turabian Style
Olubiyi, O.O., Jennifer Loschwitz and Birgit Strodel. 2020 "High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2" Preprints. https://doi.org/10.20944/preprints202004.0161.v2
Abstract
We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
Keywords
COVID-19; docking; drug repurposing; natural products; in silico drug design; viral replication inhibition
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
1 June 2020
Commenter:
Birgit Strodel
Commenter's Conflict of Interests:
Author
Comment:
We screened some further compounds and rescreened some others as we had encountered some problems with some of the compounds from DrugBank. As a result, we rewrote large parts of the Results section as some further good hits as ligands for the main protease of SARS-CoV-2 were identified.
Commenter: Birgit Strodel
Commenter's Conflict of Interests: Author