Design of Heterocyclic Compounds as Epidermal Growth Factor Receptor Inhibitors Using Molecular Docking and Interaction Fingerprint Studies

EGFR (Epidermal Growth factor receptors) expressed in different type of cancers, such as breast, esophageal, lung cancer etc. Because of their multifaceted role in cancer progression, EGFR and its related receptors have been considered as attractive targets for developing anticancer agents, i.e. EGFR inhibitors consisting molecules targeting EGFR ATP binding pocket and monoclonal antibodies targeting EGFR ligand binding domain. For patients with EGFR-mutant non-small-cell lung cancer, acquired resistance to drugs obstructs long-term therapeutic efficacy of targeted therapy. Even though third-generation medicines targeting EGFR T790M mutation have shown promise in overcoming acquired resistance to EGFR-tyrosine kinase inhibitors, fourth-generation drugs targeting acquired resistance to 3rd generation inhibitors are still needed. Hence, in present study, EGFR (PDB: 1M17) was selected as a target to perform molecular docking studies for existing ligands from literature. Interaction fingerprint analysis was applied for docked complexes. Docking studies revealed that compound 3 exhibited good binding affinity towards the selected target with XPG score-9.439Kcal/Mol among existing ligands which is comparable with that of standard drug erlotinib -9.192 Kcal/Mol. Interaction fingerprint analysis further confirmed that best docked compounds showed H-bond interaction with backbone residue of Met 769 and Cys 773 in an identical manner with that of standard drug erlotinib. Present study concludes that among selected existing compounds, the ligands containing quinazoline nucleus exhibited good binding affinity and similar binding interactions when compared with that of standard drug erlotinib and these ligands can be further optimized to increase binding affinity and interactions with the selected target.