The target of this present study is SARS-CoV-2 PLpro to explore novel potential small molecule therapeutics for COVID-19 using structure-based pharmacophore and computer aided drug design to screen the MolPort database of over 7.6 million compounds. A structure-based pharmacophore, with five important pharmacophore features, was developed using Pharmit. Further screening using hit reduction, Lipinski’s rule of five, Pharmit rank score of -8.0 or higher, and max RMSD of 1.5, led to 36 best MolPort hits out of 1426 total hits. These hits were then subjected to molecular docking through PyRX to determine the top five best hits based on docking scores and manual inspection. The top five hits were subjected to ADMET screenings through SwissADME and PreADMET to narrow down to two top hits, MolPort-046-099-656 and MolPort-004-661-970. Molecular dynamics simulations were performed using NAMD and VMD that confirmed MolPort-046-099-656’s strong interactions with the enzyme active site. Scaffold hopping was performed afterwards for the top hit using 1-Click Scaffold Hop. Five structurally similar compounds for the top hit were noted for future reference. Our findings suggest that MolPort-046-099-656 could be a potential therapeutic targeting SARS-CoV-2 PLpro.

Novel potential small molecule therapeutics of SARS-CoV-2 targeting papain-like protease

ACS Spring Meeting 2021

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