(T1030-01-09) Virtual Screening of SARS Cov 2 Papain Like Protease Inhibitors

Purpose: The spread of novel SARS-CoV-2 variants and the resulting pandemic has transformed the global economy since 2020. An effective control of the SARS-CoV-2 virus requires both vaccines and antiviral drugs . The development of antiviral treatments remains a top priority for minimizing hospitalization and COVID-19 related deaths.

Methods: The SARS-CoV-2 proteome contains several essential enzymes embedded within its non-structural proteins (nsps). The nsp3 is a large protein that harbors an essential papain-like protease (PL^pro) domain responsible for the cleavage of viral polyprotein required for viral transmission. Additionally, the nsp3/PL^pro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing the host immune response. Hence, PL^pro domain presents itself as an attractive drug-target for arresting the SARS-CoV-2 infection. Herein, we report an in silico docking study of four classes of known and previously untested anti-COVID compounds. These four classes include GRL0617, Jun, piperidine and XR8-24 analogs.

Results: We have refined a method for virtual screening these drug lead candidates. Our docking studies with 12-bound and unbound PL^pro PBD structures indicate that the holo PL^pro PDB structures exhibit ~15 % average better binding scores than unbound structures. Testing with GRL0617, piperidine, and XR8-24 analogs shows affinities on par or superior to the currently reported SARS-CoV-2 inhibitors, with an average binding score more favorable than -10 kcal/mol. Our study also reveals that each class of drug has best binding score with a specific PL^pro PDB structure.

Conclusion: Our study better illustrate the asset of virtual screening method in search for antiviral drugs.  For the most promising drug-protein complexes, FRET based assays of PL^pro inhibition and molecular dynamics simulations studies are currently underway.