Design, in Silico Evaluation, and Toxicological Assessment of $N$-Protocatechoyl Hydrazone Derivatives as Potential EGFR Kinase Inhibitors

In this study, we explored the potential of novel <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$N$</tex> protocatechoyl hydrazone derivatives as inhibitors of epidermal growth factor receptor (EGFR) kinase, a key target in cancer therapy. Using the CReM webserver, we generated 100 unique derivatives starting from compound L, all of which displayed favorable synthetic accessibility and drug-like characteristics as proven by ADME screening (with a LogP value of less than 3). Out of these, 34 compounds satisfied the Lipinski Rule of Five and were further examined for their ability to bind to EGFR using molecular docking simulations and a deep learning algorithm. Nine compounds demonstrated binding energies below –41.2 kJ/mol, surpassing the reference inhibitor Mavelertinib (MAV, –38.5 kJ/mol), and indicating their greater potential for inhibiting EGFR. The molecular docking analysis showed that the interactions were facilitated by specific amino acids such as MET793 and THR854, as well as different noncovalent forces including hydrogen bonds and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\pi-\pi$</tex> interactions. Analysis using the ProToxIII website revealed that out of the nine most promising compounds, only two, L and L1, exhibited lower anticipated toxicity than MAV. Among these, L had the biggest safety margin, with an <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\text{LD}_{50}$</tex> value of 5000 mg/kg. Based on these findings, compounds L and L1 have been identified as the most promising candidates for further in vitro testing as potential anticancer drugs.