Elucidation of significant regulatory proteins in the JNK pathway modulated by truncated pardaxin, PC6 through molecular dynamic simulation

Abstract

ABSTRACT Cancer remains a critical global health issue, with current treatments often causing significant side effects. This has spurred the search for alternative therapies, such as bioactive peptides, which offer advantages such as higher selectivity against cancer cells and ease of modification. Pardaxin, a bioactive peptide, has shown anticancer effects on various cell lines via the JNK pathway. A truncated form of pardaxin, PC6, has demonstrated anticancer properties with reduced haemolytic effects though its cell death mechanism is unclear. This study aimed to investigate PC6-induced cell death, focusing on the JNK cascade compared to parental pardaxin (PAR). JNK cascade genes were sourced from the Gene Ontology database, followed by docking screening and protein-peptide network analysis. The network identified 65 genes involved in the JNK pathway, which were verified through gene enrichment analysis. Molecular dynamic simulation and binding affinity analysis showed that PC6 had a higher affinity (−88.69, −82.17, −54.93 kcal/mol) for MAPK8, MAPK9 and HRAS proteins than PAR (−68.88, −76.64, −38.63 kcal/mol). These findings suggest that PC6 specifically interacts with these proteins to induce apoptosis via the JNK cascade, highlighting its potential as an effective anticancer agent.