Scientific article
Open access

Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits

Published inScientific reports, vol. 12, no. 1
Publication date2022-02-15
First online date2022-02-15

M pro , the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M pro inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M pro and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M pro and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M pro . The most active compound from this chemotype inhibited M pro in vitro with an IC 50 value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M pro was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.

  • X-ray crystallography
  • Screening
  • Small molecules
  • Fondation Aclon - [TH1]
Citation (ISO format)
ROSSETTI, Giacomo et al. Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits. In: Scientific reports, 2022, vol. 12, n° 1. doi: 10.1038/s41598-022-06306-4
Main files (1)
Article (Published version)
ISSN of the journal2045-2322

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