Chemical Proteomics Approaches for Screening Small Molecule Inhibitors Covalently Binding to SARS-Cov-2

Although various strategies have been used to prevent and treat SARS-CoV-2, the spread and evolution of SARS-CoV-2 is still progressing rapidly. The emerging variants Omicron and its sublineage have a greater ability to spread and escape nearly all current monoclonal antibodies treatments, highlighting an urgent need to develop therapeutics targeting current and emerging Omicron variants or recombinants with breadth and potency. Here, some small molecule drugs are rapidly identified that could covalently binding to receptor binding domain (RBD) protein of Omicron through the combined application of artificial intelligence (AI) and activity-based protein profiling (ABPP) technology. The surface plasmon resonance (SPR) and pseudo-virus neutralization experiments further reveal that an FDA-approved drug gallic acid has robust neutralization potency against Omicron pseudo-virus with the IC₅₀ values of 23.56 × 10⁻⁶ m. Taken together, a platform combining AI intelligence, biochemical, SPR, molecular docking, and pseudo-virus-based screening for rapid identification and evaluation of potential anti-SARS-CoV-2 small molecule drugs is established and the effectiveness of the platform is validated.