Exploring the binding dynamics of covalent inhibitors within active site of PL^pro in SARS-CoV-2

In the global fight against the COVID-19 pandemic caused by the highly transmissible SARS-CoV-2 virus, the search for potent medications is paramount. With a focused investigation on the SARS-CoV-2 papain-like protease (PL^pro) as a promising therapeutic target due to its pivotal role in viral replication and immune modulation, the catalytic triad of PL^pro comprising Cys111, His272, and Asp286, highlights Cys111 as an intriguing nucleophilic center for potential covalent bonds with ligands. The detailed analysis of the binding site unveils crucial interactions with both hydrophobic and polar residues, demonstrating the structural insights of the cavity and deepening our understanding of its molecular landscape. The sequence of PL^pro among variants of concern (Alpha, Beta, Gamma, Delta and Omicron) and the recent variant of interest, JN.1, remains conserved with no mutations at the active site. Moreover, a thorough exploration of apo, non-covalently bound, and covalently bound PL^pro conformations exposes significant conformational changes in loop regions, offering invaluable insights into the intricate dynamics of ligand-protein complex formation. Employing strategic in silico medication repurposing, this study swiftly identifies potential molecules for target inhibition. Within the domain of covalent docking studies and molecular dynamics, using reported inhibitors and clinically tested molecules elucidate the formation of stable covalent bonds with the cysteine residue, laying a robust foundation for potential therapeutic applications. These details not only deepen our comprehension of PL^pro inhibition but also play a pivotal role in shaping the dynamic landscape of COVID-19 treatment strategies.