A dynamic scapping workflow for RTK domains: computational modeling of natural products as dual modulators of EGFR and VEGFR signaling in breast cancer

Breast Cancer, a major global health challenge, is driven by aberrant receptor tyrosine kinase (RTK) signaling via epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). This study employs a "Dynamic Scapping" workflow, integrating molecular docking, 500 ns molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations to identify natural products with potential for dual binding to EGFR (PDB: 1M17) and VEGFR (PDB: 3VHE). From ~ 20,000 natural products, virtual screening shortlisted 13 EGFR and 12 VEGFR hits, with Digitonin, Cyclamin, Vicenin-2, Glucosylorientin, and Nicotiflorin selected for EGFR, and Quercetagetin, Silychristin, Quercetin, Scutellarein, and Isorhamnetin for VEGFR, alongside references (Erlotinib, Pyrrolopyrimidine). MD simulations, conducted as single trajectories per system, revealed stable complexes (RMSD: 1.73-2.92 Å), with Digitonin, Cyclamin, and Silychristin showing binding energies (ΔG_bind: - 84.29, - 81.47, - 63.33 kcal/mol) compared to references (Erlotinib: - 43.32 kcal/mol and Pyrrolopyrimidine: - 61.63 kcal/mol). Dynamic analyses (DCCM, PCA) indicated restricted motions, while per-residue decomposition highlighted interactions with Met769 (EGFR) and Cys919 (VEGFR). The MM/GBSA calculations excluded the entropy term, potentially affecting absolute binding energies but supporting relative ranking. These computational findings suggest Digitonin, Cyclamin, and Silychristin as candidates with the potential for dual binding to EGFR and VEGFR, addressing the need for accessible treatments globally and in regions like South Africa with high incidence rates. Experimental validation is essential to confirm their functional dual modulation and inhibitory potency for breast Cancer therapy.

Breast cancer; Dual modulators; MM/GBSA; Molecular dynamics; Natural products; RTKs.