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

ABSTRACT: 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 IC₅₀ 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.

SUBMITTER: Ferreira GM 

PROVIDER: S-EPMC9270405 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature