tetano
Editor, Senior Moderator
Sci Rep
. 2020 Nov 30;10(1):20808.
doi: 10.1038/s41598-020-77794-5.
Conserved interactions required for inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Alina Shitrit[SUP] 1 [/SUP], Daniel Zaidman[SUP] 2 [/SUP], Ori Kalid[SUP] 3 [/SUP], Itai Bloch[SUP] 4 [/SUP], Dvir Doron[SUP] 5 [/SUP], Tali Yarnizky[SUP] 6 [/SUP], Idit Buch[SUP] 7 [/SUP], Idan Segev[SUP] 8 [/SUP], Efrat Ben-Zeev[SUP] 9 [/SUP], Elad Segev[SUP] 10 [/SUP], Oren Kobiler[SUP] 11 [/SUP]
Affiliations
Abstract
The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands' interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 ?M concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.
. 2020 Nov 30;10(1):20808.
doi: 10.1038/s41598-020-77794-5.
Conserved interactions required for inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Alina Shitrit[SUP] 1 [/SUP], Daniel Zaidman[SUP] 2 [/SUP], Ori Kalid[SUP] 3 [/SUP], Itai Bloch[SUP] 4 [/SUP], Dvir Doron[SUP] 5 [/SUP], Tali Yarnizky[SUP] 6 [/SUP], Idit Buch[SUP] 7 [/SUP], Idan Segev[SUP] 8 [/SUP], Efrat Ben-Zeev[SUP] 9 [/SUP], Elad Segev[SUP] 10 [/SUP], Oren Kobiler[SUP] 11 [/SUP]
Affiliations
- PMID: 33257760
- DOI: 10.1038/s41598-020-77794-5
Abstract
The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands' interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 ?M concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.