In-silico identification and exploration of small molecule coumarin-1,2,3-triazole hybrids as potential EGFR inhibitors for targeting lung cancer.

Globally, lung cancer is a significant public health concern due to its role as the leading cause of cancer-related mortalities. The promising target of EGFR for lung cancer treatment has been identified, providing a potential avenue for more effective therapies. The purpose of the study was to design a library of 1843 coumarin-1,2,3-triazole hybrids and screen them based on a designed pharmacophore to identify potential inhibitors targeting EGFR in lung cancer with minimum or no side effects. Pharmacophore-based screening was carried out and 60 hits were obtained. To gain a better understanding of the binding interactions between the compounds and the targeted receptor, molecular docking was conducted on the 60 screened compounds. In-silico ADME and toxicity studies were also conducted to assess the drug-likeness and safety of the identified compounds. The results indicated that coumarin-1,2,3-triazole hybrids COUM-0849, COUM-0935, COUM-0414, COUM-1335, COUM-0276, and COUM-0484 exhibit dock score of - 10.2, - 10.2, - 10.1, - 10.1, - 10, - 10 while reference molecule - 7.9 kcal/mol for EGFR (PDB ID: 4HJO) respectively. The molecular docking and molecular dynamics simulations revealed that the identified compounds formed stable interactions with the active site of EGFR, indicating their potential as inhibitors. The in-silico ADME and toxicity studies showed that the compounds had favorable drug-likeness properties and low toxicity, further supporting their potential as therapeutic agents. Finally, we performed DFT studies on the best-selected ligands to gain further insights into their electronic properties. The findings of this study provide important insights into the potential of coumarin-1,2,3-triazole hybrids as promising EGFR inhibitors for the management of lung cancer.