tetano
Editor, Senior Moderator
Eur J Med Chem
. 2022 Jan 23;231:114130.
doi: 10.1016/j.ejmech.2022.114130. Online ahead of print.
In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease
Muya Xiong[SUP] 1 [/SUP], Tianqing Nie[SUP] 2 [/SUP], Qiang Shao[SUP] 3 [/SUP], Minjun Li[SUP] 4 [/SUP], Haixia Su[SUP] 5 [/SUP], Yechun Xu[SUP] 6 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL[SUP]pro[/SUP]) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CL[SUP]pro[/SUP]. Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL[SUP]pro[/SUP] in complex with compound 8, the most potent hit with an IC[SUB]50[/SUB] value of 8.50 μM, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed interactions of the compound with S1' and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CL[SUP]pro[/SUP], but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.
Keywords: Covalent inhibitor; Crystal structure; SARS-CoV-2 3C-Like protease; Virtual screening.
. 2022 Jan 23;231:114130.
doi: 10.1016/j.ejmech.2022.114130. Online ahead of print.
In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease
Muya Xiong[SUP] 1 [/SUP], Tianqing Nie[SUP] 2 [/SUP], Qiang Shao[SUP] 3 [/SUP], Minjun Li[SUP] 4 [/SUP], Haixia Su[SUP] 5 [/SUP], Yechun Xu[SUP] 6 [/SUP]
Affiliations
- PMID: 35114541
- DOI: 10.1016/j.ejmech.2022.114130
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL[SUP]pro[/SUP]) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CL[SUP]pro[/SUP]. Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL[SUP]pro[/SUP] in complex with compound 8, the most potent hit with an IC[SUB]50[/SUB] value of 8.50 μM, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed interactions of the compound with S1' and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CL[SUP]pro[/SUP], but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.
Keywords: Covalent inhibitor; Crystal structure; SARS-CoV-2 3C-Like protease; Virtual screening.