A Comprehensive Computational Investigation of Novel HydrazideHydrazone Derivatives as Potential EGFR Inhibitors for Gastric Cancer Treatment

Rákkutatás · Gastric cancer · EGFR

The best 3D-QSAR model was built using PLS and comparative molecular similarity index analysis (CoMSIA), with proven robust predictive accuracy (Q^2 = 0.651, R^2 = 0.912, and R^2_test = 0.937).

The epidermal growth factor receptor (EGFR) is a confirmed therapeutic target, as mutations alter its expression, reduce apoptotic function, and enhance cancer cell proliferation, including in gastric cancer. Because EGFR mutations alter the binding affinity and selectivity of therapeutic agents, we investigated several hydrazide-hydrazone derivatives for their structural and chemical bioactivity towards EGFR by combining 3D-QSAR analysis, molecular docking, ADMET profiling, and molecular dynamics simulations, and optimized the best-performing derivative as a novel anti-gastric cancer drug candidate. The best 3D-QSAR model was built using PLS and comparative molecular similarity index analysis (CoMSIA), with proven robust predictive accuracy (Q^2 = 0.651, R^2 = 0.912, and R^2_test = 0.937). COMSIA's contour maps were used to identify four candidate compounds (M1, M2, M3, and M6) that indicated the most promising sites for anticancer activity. ADMET profiling confirmed the drug-likeness and therapeutic suitability of the optimized compounds, with most displaying favorable pharmacokinetics behavior as well as no predicted toxicological concerns for any of the proposed compounds. To examine ligand-receptor interactions and binding affinities, molecular docking studies were performed against the EGFR crystal structure (PDB: 4HJO). Among the derivatives, compounds M3 and M6 showed strong affinity for the target protein with energies of -10.8 kcal‑mol and -10.4 kcal‑mol, respectively, and formed important interactions with key residues such as MET A: 769, THR A: 830, and LYS A: 721. MD simulations over 100 ns proved the structural stability of both complexes, EGFR‑M3 and EGFR‑M6. While MM-GBSA analysis revealed that M3 was the most energetically favorable binder. (ΔG = -28.14 kcal‑mol). These findings support the Hydrazidehydrazone derivatives' potential as EGFR kinase inhibitors, with M3 emerging as a particularly promising lead compound.

Bizonyítékszint: Számítógépes vagy elméleti. Modellből vagy adatbányászatból származó jel.

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