Evaluation in silico of the (pBthTX-I)2K Peptide as a SARS-CoV-2 PL proProtease inhibitor

Abstract Context Since 2019, the COVID-19 pandemic, caused by SARS-CoV-2, has resulted in millions of cases and deaths worldwide. The virus has various essential proteins for its replication and immune evasion, including non-structural protein 3 (nsp3), which encodes the papain-like protease (PLpro). PLpro plays a crucial role in processing the viral polyprotein pp1a and in interfering with the immune system through deubiquitination, making it a strategic target for antiviral development. Inhibiting PLpro is particularly relevant as it can block viral replication and modulate the immune response, interfering with the progression of the infection. In this context, our study investigated the inhibitory potential of a non-toxic dimeric peptide derived from Bothopstoxin-I, (pBthTX-I)2K, as an inhibitor of SARS-CoV-2 PLpro. Methods The investigation utilized molecular docking techniques and molecular dynamics (MD) simulations to analyze the interactions of the peptide (pBthTX-I)2K with SARS-CoV-2 PLpro. The structural model of PLpro was constructed based on crystallographic data and validated through homology modeling. Docking analysis was performed using the HPEPDOCK software, revealing a high binding affinity between (pBthTX-I)2K and PLpro, with binding scores of -197.6 kcal.mol-1 for the homology model (MPL) and − 197.0 kcal.mol-1 for the crystallographic model (CPL). The primary interactions between the peptide and PLpro were analyzed, highlighting the formation of hydrogen bonds and hydrophobic interactions with key enzyme residues. To assess the stability of the formed complexes, molecular dynamics simulations were conducted for 300 ns, utilizing the appropriate force field for proteins and peptides, confirming the reliability of the homology model (MPL) in comparison to the crystallographic model (CPL).