Inhibitor induced conformational changes in SARS-COV-2 papain-like protease

SARS-CoV-2’s papain-like protease (PL(pro)) interaction with ligands has recently been explored with a myriad of crystal structures. We used molecular dynamics (MD) simulations to study different PL(pro)-ligand complexes, their ligand-induced conformational changes, and interactions. We focused on inhibitors reported with known IC(50) against PL(pro), namely GRL-0617, XR8-89, PLP_Snyder530, and Sander’s recently published compound 7 (CPD7), and compared these trajectories against the apostructure (Apo), with a total of around 60 µs worth simulation data. We aimed to study the conformational changes using molecular dynamics simulations for the inhibitors in the PL(pro). PCA analyses and the MSM models revealed distinct conformations of PL(pro) in the absence/presence of ligands and proposed that BL2-loop contributes to the accessibility of these inhibitors. Further, bulkier substituents closer to Tyr268 and Gln269 could improve inhibition of SARS-CoV-2 PL(pro) by occupying the region between BL2-groove and BL2-loop, but we also expand on the relevance of exploring multiple PL(pro) sub-pockets to improve inhibition.