Inhibitor induced conformational changes in SARS-COV-2 papain-like protease
Gláucio Monteiro Ferreira, Thanigaimalai Pillaiyar, Mário Hiroyuki Hirata, Antti Poso, Thales Kronenberger
Abstract
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 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.