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In Silico Analysis of H-Lys-Asp-OH Dipeptide: DFT Optimization, Frontier Orbitals, Electrostatic Potential, EGFR/HER2 Docking and ADMET Profiling

Year 2025, Volume: 46 Issue: 4, 974 - 989, 30.12.2025

Aliye Demet Demirağ

https://doi.org/10.17776/csj.1636562

Abstract

Cancer remains a significant health problem as a pathological process driven by complex molecular mechanisms leading to cellular homeostasis disruption. In this complex process, abnormal activation of receptor tyrosine kinases stands out, with hyperactivation of Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) strongly associated with aggressive tumor phenotypes and poor clinical outcomes in many cancer types. Considering the resistance development and side effect problems frequently encountered in current targeted therapies, understanding the molecular interactions of this unique dual interaction mechanism dipeptide with EGFR and HER2 is critically important for developing new and effective treatment strategies. In this study, the structural characterization, receptor interactions, and pharmacokinetic properties of the H-Lys-Asp-OH dipeptide were investigated using computational methods. Using DFT/B3LYP/6-311++G(d,p), AutoDock Vina, QikProp, and OSIRIS methods, binding energies of -6.2 kcal/mol for EGFR and -6.3 kcal/mol for HER2, a HOMO-LUMO gap of 5.701 eV, LogP = -4.151, and 0% oral absorption were obtained. Despite poor oral bioavailability, this dipeptide acts as a promising scaffold for further optimization. These findings demonstrate the potential of H-Lys-Asp-OH as a dual EGFR/HER2 inhibitor scaffold and provide a framework for designing targeted therapeutics with improved selectivity profiles.

Keywords

Dual kinase inhibition EGFR/HER2 targeting Peptide-based therapeutics Molecular docking ADMET

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Details

Primary Language English
Subjects Atomic and Molecular Physics
Journal Section Research Article
Authors

Aliye Demet Demirağ 0000-0002-9609-9150

Submission Date February 10, 2025
Acceptance Date December 5, 2025
Publication Date December 30, 2025
Published in Issue Year 2025 Volume: 46 Issue: 4

Cite

APA Demirağ, A. D. (2025). In Silico Analysis of H-Lys-Asp-OH Dipeptide: DFT Optimization, Frontier Orbitals, Electrostatic Potential, EGFR/HER2 Docking and ADMET Profiling. Cumhuriyet Science Journal, 46(4), 974-989. https://doi.org/10.17776/csj.1636562

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