tetano
Editor, Senior Moderator
Sci Rep
. 2022 Feb 15;12(1):2505.
doi: 10.1038/s41598-022-06306-4.
Non-covalent SARS-CoV-2 M [SUP]pro[/SUP] inhibitors developed from in silico screen hits
Giacomo G Rossetti[SUP] 1 2 [/SUP], Marianna A Ossorio[SUP] 1 [/SUP], Stephan Rempel[SUP] 2 [/SUP], Annika Kratzel[SUP] 3 4 5 [/SUP], Vasilis S Dionellis[SUP] 1 [/SUP], Samia Barriot[SUP] 1 [/SUP], Laurence Tropia[SUP] 1 [/SUP], Christoph Gorgulla[SUP] 6 7 8 [/SUP], Haribabu Arthanari[SUP] 6 8 [/SUP], Volker Thiel[SUP] 3 4 [/SUP], Peter Mohr[SUP] 9 [/SUP], Remo Gamboni[SUP] 9 [/SUP], Thanos D Halazonetis[SUP] 10 11 [/SUP]
Affiliations
Abstract
M[SUP]pro[/SUP], 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M[SUP]pro[/SUP]. The most active compound from this chemotype inhibited M[SUP]pro[/SUP] in vitro with an IC[SUB]50[/SUB] value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M[SUP]pro[/SUP] 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.
. 2022 Feb 15;12(1):2505.
doi: 10.1038/s41598-022-06306-4.
Non-covalent SARS-CoV-2 M [SUP]pro[/SUP] inhibitors developed from in silico screen hits
Giacomo G Rossetti[SUP] 1 2 [/SUP], Marianna A Ossorio[SUP] 1 [/SUP], Stephan Rempel[SUP] 2 [/SUP], Annika Kratzel[SUP] 3 4 5 [/SUP], Vasilis S Dionellis[SUP] 1 [/SUP], Samia Barriot[SUP] 1 [/SUP], Laurence Tropia[SUP] 1 [/SUP], Christoph Gorgulla[SUP] 6 7 8 [/SUP], Haribabu Arthanari[SUP] 6 8 [/SUP], Volker Thiel[SUP] 3 4 [/SUP], Peter Mohr[SUP] 9 [/SUP], Remo Gamboni[SUP] 9 [/SUP], Thanos D Halazonetis[SUP] 10 11 [/SUP]
Affiliations
- PMID: 35169179
- DOI: 10.1038/s41598-022-06306-4
Abstract
M[SUP]pro[/SUP], 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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[SUP]pro[/SUP] and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M[SUP]pro[/SUP]. The most active compound from this chemotype inhibited M[SUP]pro[/SUP] in vitro with an IC[SUB]50[/SUB] value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M[SUP]pro[/SUP] 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.