Synthesis, characterization, and in silico studies of new benzohydrazide derivatives targeting EGFR kinase
TL;DR
These compounds represent computationally prioritized EGFR-directed scaffolds for experimental validation rather than confirmed EGFR inhibitors.
Abstract
Targeted therapy has improved the management of non-small cell lung cancer (NSCLC); however, resistance and suboptimal responses persist, requiring the development of new epidermal growth factor receptor (EGFR)-directed chemotypes. A series of benzohydrazide derivatives (3a–f) was synthesized and characterized using FT-IR, 1 H NMR, and 13 C NMR. In silico ADME profiling predicted high oral absorption for the series and acceptable MW/HBD/HBA ranges; however, the elevated predicted lipophilicity (QPlogPo/w > 5) suggested potential solubility and nonspecific binding risks. Compound 3e had the most balanced size and polarity profile, and compound 3f had the highest predicted permeability. Binding was evaluated against two EGFR kinase conformations (PDB: 1M17, active-like; 4HJO, inactive-like) using /native-ligand redocking, docking/induced-fit docking, Prime MM-GBSA, and 200 ns molecular dynamics simulations, together with three EGFR reference inhibitors and five DUD-E decoys. The docking/MM-GBSA results suggested conformation-dependent binding, with 3d favored in 1M17 and 3f in 4HJO, with recurrent ATP-site contacts. Overall, these compounds represent computationally prioritized EGFR-directed scaffolds for experimental validation rather than confirmed EGFR inhibitors.