Docking-based virtual screening studies aiming at the covalent inhibition of SARS-CoV-2 MPro by targeting the cysteine 145. (June 2021)

• Record Type: Journal Article
• Authors: Soulère, Laurent; Barbier, Thibaut; Queneau, Yves
• Is Part Of: Computational biology and chemistry. Volume 92(2021)
• Publication Date: 2021-06
• Subjects: SARS-CoV-2 -- Covalent inhibitors -- MPro -- Flexible docking -- Virtual screening; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2021.107463
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Docking studies of three known covalent inhibitors allow validation of the virtual screening method. Docking studies of soft electrophilic compounds led to the identification of 17 potential covalent inhibitors. Dimethylfumarate, fosfomycin, ibrutinib and saxagliptin were identified as potential covalent drugs. Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 which has infected millions of people worldwide. The main protease of SARS-CoV-2 (M Pro ) has been recognized as a key target for the development of antiviral compounds. Taking advantage of the X-ray crystal complex with reversible covalent inhibitors interacting with the catalytic cysteine 145 (Cys145), we explored flexible docking studies to select alternative compounds able to target this residue as covalent inhibitors. First, docking studies of three known electrophilic compounds led to results consistent with co-crystallized data validating the method for SARS-CoV-2 M Pro covalent inhibition. Then, libraries of soft electrophiles (overall 41 757 compounds) were submitted to docking-based virtual screening resulting in the identification of 17 molecules having their electrophilic group close to the Cys145 residue. We also investigated flexible docking studies of a focused approved covalent drugs library including 32 compounds with various electrophilic functional groups. Among them, the calculations resulted in the identification of four compounds, namely dimethylfumarate, fosfomycin, ibrutinib and saxagliptin, able first, to bind to the active site of the protein and second, to form a covalent bond with the catalytic cysteine.