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In Vitro and In Silico Assessment of Anticancer Activity of Venom-Derived and Biomimetic Neurotransmitter Inhibitor
Dilan Akhan1,2, Bilge Bicak1, Gizem Akman3
1Department of Physics, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Türkiye.
Abstract:
Cancer, resulting from uncontrolled cell proliferation, is a leading cause of death worldwide and its incidence continues to rise. Challenges such as late diagnosis, aggressive tumor biology, and therapeutic resistance limit the effectiveness of current treatment strategies. Therefore, therapeutic peptides capable of penetrating cells and exhibiting high target specificity have emerged as an innovative approach in cancer therapy. Peptides derived from animal venoms have demonstrated antitumor activity and diagnostic potential in glioma, colon, ovarian, breast, and prostate cancers; for instance, chlorotoxin, crotamine, and eosinophil-derived neurotoxin are being investigated as biomarkers or target-specific anticancer agents. Critical signaling pathways in cancer cells, including PI3K/Akt/mTOR, EGFR, androgen receptor, PSMA, and CDK8, have been explored as targets for peptide-based therapeutics in both in silico and experimental studies. In this study, the anticancer potential of Vialox (Gly-Pro-Arg-Pro-Ala) derived from Tropidolaemus wagleri venom and Leuphasyl (Tyr-Ala-Gly-Phe-Leu) derived from botulinum neurotoxin as a biommimetic peptide were evaluated through molecular docking, MM-GBSA calculations, molecular dynamics simulations, ADMET analysis, and MTT cell assays. Docking studies revealed strong binding affinities of Vialox and Leuphasyl to key oncogenic targets, with docking scores ranging from -10.63 to -7.59 kcal/mol. The highest binding was observed for EGFR-Leuphasyl (-10.63 kcal/mol), followed by Vialox-EGFR (-9.24 kcal/mol). PI3K docking scores were also high, with -9.05 and -9.15 kcal/mol for Vialox and Leuphasyl, respectively. ADMET predictions indicated limited oral bioavailability and minimal BBB penetration. MM-GBSA calculations showed that Vialox and Leuphasyl interact differently with the EGFR binding pocket. Vialox binding is mainly driven by electrostatic interactions, with a binding energy of -65.29 kcal/mol. Leuphasyl relies on hydrophobic interactions but has a lower binding energy of -46.68 kcal/mol due to differences in charge distribution and polar interactions. In vitro MTT assays showed that both peptides exhibited the most pronounced cytotoxic effects in MDA-MB-231 and PC3 cells, supporting their potential selective anticancer activity. The findings suggest that both peptides may exhibit selective anticancer effects, and that combining in silico approaches with experimental validation represents an effective strategy for developing novel peptide-based cancer therapeutics.
Insights
This study explores novel peptide therapeutics, Vialox and Leuphasyl, for cancer treatment. Both peptides show promising anticancer activity against specific cancer cell lines, suggesting potential for targeted cancer therapy development.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer is a leading cause of death due to uncontrolled cell proliferation, with current treatments facing challenges like resistance and late diagnosis.
- Therapeutic peptides offer innovative cancer treatment strategies, especially those derived from animal venoms, showing potential in various cancer types.
- Targeting critical cancer cell signaling pathways like PI3K/Akt/mTOR and EGFR is a key focus for developing effective peptide-based therapeutics.
Purpose of the Study:
- To evaluate the anticancer potential of Vialox and Leuphasyl peptides against key oncogenic targets.
- To investigate the binding affinities and interaction mechanisms of these peptides with cancer-related proteins using computational methods.
- To assess the in vitro cytotoxic effects of Vialox and Leuphasyl on specific cancer cell lines.
Main Methods:
- In silico molecular docking and MM-GBSA calculations were used to assess binding affinities to targets like EGFR and PI3K.
- Molecular dynamics simulations and ADMET analysis were performed to understand peptide-target interactions and pharmacokinetic properties.
- In vitro MTT assays were conducted to determine the cytotoxic effects of the peptides on cancer cells.
Main Results:
- Vialox and Leuphasyl exhibited strong binding affinities to oncogenic targets, with significant scores for EGFR and PI3K.
- EGFR-Leuphasyl showed the highest binding affinity (-10.63 kcal/mol), followed by Vialox-EGFR (-9.24 kcal/mol).
- In vitro assays demonstrated pronounced cytotoxic effects of both peptides on MDA-MB-231 and PC3 cancer cells, indicating selective anticancer activity.
Conclusions:
- Vialox and Leuphasyl show significant potential as selective anticancer agents, particularly against EGFR and PI3K pathways.
- Computational and experimental approaches combined effectively identified promising peptide candidates for cancer therapy.
- Further development of these peptides could lead to novel, targeted peptide-based cancer therapeutics.
