Datura stramonium defensin-like peptide computationally targets EGFR, ERBB2, and VEGFR-3 with stable binding

Targeting receptor tyrosine kinases (RTKs) like EGFR, ERBB2, and VEGFR-3 is crucial for cancer therapy, as they drive tumor growth, survival, and angiogenesis. Despite existing treatments, challenges such as drug resistance, systemic toxicity, and high costs persist, necessitating the discovery of novel, multi-target therapeutic agents. Natural products, particularly peptides, offer a rich source for developing compounds with high specificity and potentially lower toxicity profiles, addressing the urgent need for innovative anticancer strategies.

Researchers computationally characterized a novel defensin-like peptide (DEFL), 74 amino acids long, isolated from Datura stramonium (GenBank accession KT371458). They performed molecular docking simulations to assess its binding affinity to EGFR, ERBB2, and VEGFR-3. To evaluate complex stability, 100 ns molecular dynamics (MD) simulations were conducted. Key metrics included Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), radius of gyration, hydrogen bond profiling, Dynamic Cross-Correlation Map (DCCM), and Principal Component Analysis (PCA).

Molecular docking simulations revealed favorable binding scores for the defensin-like peptide across all target receptors: -80.6 ± 10.6 for EGFR, -63.6 ± 7.4 for ERBB2, and -50.5 ± 6.7 for VEGFR-3. These interactions involved residues within predicted receptor-binding regions. Molecular dynamics simulations confirmed stable peptide-receptor complexes over 100 ns. RMSD profiles showed EGFR stabilizing around 0.6-0.8 nm, ERBB2 around 0.7-0.9 nm, and VEGFR-3 exhibiting tighter stability at 0.3-0.4 nm. Ligand RMSDs indicated moderate flexibility for ERBB2 (peaks up to 1.3 nm) but tighter stability for VEGFR-3 (0.3-0.5 nm).