In silico design and discovery of pan coronavirus small molecule anti-virals targeting 3CL^PRO protease

Coronaviruses (CoV), belonging to the family Coronaviridae, were not considered dangerous pathogens until the outbreaks of SARS, MERS, and more recently, COVID-19. The coronaviruses causing these respective diseases/syndromes, SARS, MERS, and SARS-CoV2, share high sequence and structural similarities. COVID-19 continues to have a global impact on human health and the economy. Human-to-human transmission is at the center of COVID-19's ability to stall the entire world and force lockdowns across the globe. The corona viruses' positive sense RNA genome is ∼30 kb long and encodes non-structural (ORF1ab) and structural (Spike, Envelope, Membrane, and Nucleo-capsid) proteins. The main viral protease (NSP5) is a Chymotrypsin-like protease (3CL^pro) that cleaves on the carboxy side of the glutamine (Q) of the polypeptide sequence motif x-(L/F/M)-Q-(G/A/S)-x. 3CL^PRO is highly conserved among coronaviruses and is critical in the replication and viral life cycle. Therefore, 3CL^PRO is considered a promising drug target. We have recently reported three natural compounds, flavonoid derivatives, to target the cysteine 145 of the catalytic dyad covalently. Here, we have screened for small molecules with pan coronavirus activity to target 3CL^pro. Our rigid body docking studies have identified 30 small molecules with comparable binding affinities to all the beta coronaviruses. Of these, five molecules have showed the possibility of covalently attacking the C145 of the catalytic dyad. MD simulations have revealed compounds 22 and 23 to be the most ideal lead compounds. Interestingly, one of the compounds, 22, identified in the current study has already shown to be an ideal lead compound against SARS-CoV2 3CL^PRO.