In silico discovery and interaction analysis of a Datura stramonium defensin-like peptide targeting cancer-related receptors.
TL;DR
Overall, the simulations indicate persistent peptide-receptor association and stable structural behavior of the complexes at the computational level, however, molecular docking and molecular dynamics simulations do not demonstrate functional inhibition of EGFR, ERBB2, or VEGFR-3, nor do they confirm anticancer efficacy.
Abstract
Cancer continues to be a major global health burden, with receptor tyrosine kinases such as EGFR, ERBB2, and VEGFR-3 being critical therapeutic targets due to their central roles in tumor growth, survival, and angiogenesis. Current therapies, while effective in some contexts, face limitations including resistance, toxicity, and high cost, highlighting the need for novel multi-target approaches. In this study, we report the isolation and computational characterization of a novel defensin-like peptide (DEFL) from Datura stramonium (GenBank accession KT371458). The peptide sequence encoded 74 amino acids and displayed characteristic cysteine-stabilized motifs. Docking simulations revealed favorable binding scores toward EGFR (- 80.6 ± 10.6), ERBB2 (- 63.6 ± 7.4), and VEGFR-3 (- 50.5 ± 6.7), with interactions involving residues located within predicted receptor-binding regions. To further assess stability, 100 ns molecular dynamics simulations were performed. RMSD profiles confirmed stable complexes, with EGFR stabilizing around 0.6-0.8 nm, ERBB2 around 0.7-0.9 nm, and VEGFR-3 at a tighter 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). RMSF analyses revealed minimal fluctuations (< 0.3 nm) at binding sites, and radius of gyration values remained stable, indicating compact receptor-peptide complexes (EGFR: 3.45-3.75 nm; ERBB2: 2.95-3.20 nm; VEGFR-3: 1.92-1.98 nm). Hydrogen bond profiling and additional trajectory analyses (DCCM and PCA) supported overall system equilibration without major structural disruption during the simulations. The Datura stramonium defensin-like peptide indicating a stable and energetically favorable peptide-receptor interactions at the computational level. Overall, the simulations indicate persistent peptide-receptor association and stable structural behavior of the complexes at the computational level. However, molecular docking and molecular dynamics simulations do not demonstrate functional inhibition of EGFR, ERBB2, or VEGFR-3, nor do they confirm anticancer efficacy. Therefore, these results should be interpreted strictly as hypothesis-generating in silico predictions, and experimental validation, including peptide synthesis, receptor-binding assays, extracellular-domain competition assays, and cancer cell-based functional studies, will be required to confirm biological relevance.