De novo Design of SARS-CoV-2 Main Protease Inhibitors

Abstract

The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, M^Pro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar non-covalent inhibitors of the viral main protease.

Keywords: Coronavirus; Molecular Modeling; SARS-CoV-2; Small-Molecule Inhibitor; Viral Main Protease.

Figure 1.

a) Computational lead identification (red) by optimizing initial hits in the ASINEX screening (blue). b) Representative target compounds 1-3 with excellent docking scores.

Figure 2.

Synthesized pyridone esters 4’, 6a-v to inhibit the SARS-CoV-2 main protease and investigate the structure-activity relationship of the scaffold.

Scheme 1.

Assembly of initially identified compounds 1-3.

Scheme 2.

Derivatizing the pyridone side chain of the nitrile and anisole analog.

Scheme 3.

a) As the carboxylic acid 22a loses significant activity, amides 23a-c and 24a/b have been synthesized. b) Outline of the synthesis route to the highly active SARS-CoV-2 M^Pro inhibitor 28.