Identification and exploration of quinazoline-1,2,3-triazole inhibitors targeting EGFR in lung cancer.

Epidermal growth factor receptor (EGFR) enhances lung cancer development, due to their inability to permeate the cell membrane, secreted growth factors work through specialized signal transduction pathways. The purpose of this study is to find out a novel anticancer agent that inhibits EGFR and reduces the chances of lung cancer. A series of triazole-substituted quinazoline hybrid compounds were designed by Chemdraw software and docked against five different crystallographic EGFR tyrosine kinase domain (TKD). For docking and visualization PyRx, Autodock vina, and Discovery studio visualizer were used. Molecule-14, Molecule-16, Molecule-19, Molecule-20, and Molecule-38 showed significant affinity but Molecule-19 showed excellent binding affinity (-12.4 kcal/mol) with crystallographic EGFR tyrosine kinase. The superimposition of the co-crystalized ligand with the hit compound shows similar conformation at the active site of EGFR (PDB ID: 4HJO) indicating excellent coupling and pharmaceutically active. The hit compound showed a good bioavailability score (0.55) with no sign of carcinogenesis, mutagenesis, or reproductive toxicity properties. MD simulation and MMGBSA represent good stability and binding free energy demonstrating that the hit (Molecule-19) may be used as a lead compound. Molecule-19 also showed good ADME properties, bioavailability scores, and synthetic accessibility with fewer signs of toxicity. It was observed that Molecule-19 may be a novel and potential inhibitor against EGFR with fewer side effects than the reference molecule. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about the amino acid residues involved in binding. Overall, this study led to the identification of potential EGFR inhibitors with favorable pharmacokinetic properties. We believe that the outcome of this study can help to develop more potent drug-like molecules to tackle human lung cancer.