Vialox and Leuphasyl pentapeptides show potent in silico anticancer activity against EGFR and PI3K pathways

Despite advancements, cancer remains a leading cause of death globally, with current treatments often limited by late diagnosis, aggressive tumor biology, and therapeutic resistance. This necessitates innovative approaches, and therapeutic peptides capable of cell penetration and high target specificity have emerged as promising candidates. Peptides derived from animal venoms, such as chlorotoxin, have shown antitumor activity and diagnostic potential across various cancers. Key oncogenic signaling pathways like PI3K/Akt/mTOR, EGFR, and androgen receptor are critical targets for developing novel peptide-based therapeutics.

Researchers evaluated the anticancer potential of two pentapeptides: Vialox (Gly-Pro-Arg-Pro-Ala), derived from Tropidolaemus wagleri venom, and Leuphasyl (Tyr-Ala-Gly-Phe-Leu), a biomimetic peptide from botulinum neurotoxin. Their activity was assessed through a multi-faceted approach including molecular docking, MM-GBSA calculations, molecular dynamics simulations, and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis. The study also included MTT cell assays to evaluate cellular effects, though specific results were not detailed in the abstract. Key oncogenic targets investigated were EGFR and PI3K.

Molecular docking studies revealed strong binding affinities for both Vialox and Leuphasyl to key oncogenic targets, with docking scores ranging from -10.63 to -7.59 kcal/mol. The highest binding affinity was observed for Leuphasyl with EGFR at -10.63 kcal/mol, closely followed by Vialox with EGFR at -9.24 kcal/mol. Binding to PI3K was also significant, with scores of -9.05 kcal/mol for Vialox and -9.15 kcal/mol for Leuphasyl. MM-GBSA calculations further elucidated distinct binding mechanisms: Vialox binding to EGFR was primarily driven by electrostatic interactions, yielding a binding energy of -65.29 kcal/mol. In contrast, Leuphasyl relied more on hydrophobic interactions within the EGFR binding pocket. ADMET predictions indicated limited oral bioavailability and minimal blood-brain barrier (BBB) penetration for both peptides. Although MTT cell assays were performed, specific quantitative results from these experiments were not provided in the abstract.

Leuphasyl exhibited the strongest binding affinity to EGFR at -10.63 kcal/mol, highlighting its potent inhibitory potential against a critical cancer pathway.