Identification of non-covalent 3C-like protease inhibitors against severe acute respiratory syndrome coronavirus-2 via virtual screening of a Korean compound library

Abstract

The outbreak of coronavirus (CoV) disease 2019 (COVID-19) caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has turned into a pandemic. The enzyme 3C-like protease (3CL^pro) is essential for the maturation of viral polyproteins in SARS-CoV-2 and is therefore regarded as a key drug target for treating the disease. To identify 3CL^pro inhibitors that can suppress SARS-CoV-2 replication, we performed a virtual screening of 500,282 compounds in a Korean compound bank. We then subjected the top computational hits to inhibitory assays against 3CL^pro in vitro, leading to the identification of a class of non-covalent inhibitors. Among these inhibitors, compound 7 showed an EC₅₀ of 39.89 μM against SARS-CoV-2 and CC₅₀ of 453.5 μM. This study provides candidates for the optimization of potent 3CL^pro inhibitors showing antiviral effects against SARS-CoV-2.

Keywords: 3C-like protease; Antivirals; Coronavirus disease 2019; Inhibitors; Severe acute respiratory syndrome coronavirus 2.

Graphical abstract

Fig. 1

Predicted binding models of compounds 3 and 7 with SARS-CoV-2 3CL^pro. (A) Binding of compound 3 (yellow) and (B) compound 7 (orange) to the SARS-CoV-2 3CL^pro (grey). For clarity, key binding site residues are illustrated as sticks and labeled using the 3-letter amino acid codes. The hydrogen bonds are displayed as green lines with dashes, and hydrophobic interactions are shown as pink lines with dashes. The electrostatic interactions are indicated using orange lines with dashes.