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.
【초록키워드】 SARS-CoV-2, molecular dynamics, protease, molecular dynamics simulations, inhibitors, Molecular dynamics simulation, Papain-like protease, Accessibility, trajectory, molecular, inhibitor, interactions, Ligand, Interaction, Analysis, conformational change, PCA, crystal structures, ligands, conformation, Papain, myriad, conformational changes, IMPROVE, reported, contribute, complexes, expand, 【제목키워드】 Papain-like protease, conformational change,