In Silico Evaluation of Molecular Docking, Molecular Dynamic, and ADME Study of New Nabumetone Schiff Base Derivatives (1,3,4-oxadiazole or 1,3,4-thiadiazole ring) Promising Antiproliferation Action Against Lung Cancer

Abstract

A total of eight novel Nabumetone Schiff Base Derivatives with 1,3,4-oxadiazole or 1,3,4-thiadiazole rings have been proposed to evaluate their potential effectiveness against the epidermal growth factor receptor (EGFR). Molecular docking was conducted with the crystalline structure of EGFR (code: 4HJO), wherein the eight compounds of Nabumetone Schiff Base Derivatives with 1,3,4-oxadiazole or 1,3,4-thiadiazole ring derivatives docked to determine their binding affinity to the target binding site. Using GOLD software (CCDC) version 5.43, computer predictions were made, and the compounds were designed using ChemDraw version 22.2 (professional version). Subsequently, their selectivity with EGFR was assessed, with erlotinib selected as a control for comparison. In silico ADME studies were conducted, revealing the significant potential for binding, and drug-likeness was assessed using the Swiss ADME website. Additionally, Molecular Dynamic simulations of compound N3 complexes with EGFR were performed using Schrodinger Suite 2023 software for 50 ns, estimating RMSD, RMSF, Ligand-Protein Contacts, and Ligand Torsion Profile results. Result Showing the best binding energy within receptor pocket with a promising activity against EGFR protein receptor. The highest PLP fitness levels were found in compounds N1, N2, and N3 for lung cancer cell protein (89.1, 89.02, and 87.95, respectively, average value), All compounds were found to adhere to Lipinski's rule of five, with high absorption from the gastrointestinal tract (except N4), and none of the proposed compounds were able to pass through the blood-brain barrier. Molecular dynamic result, Mean Protein RMSD 1.8 Å, ligand RMSD 1.6 Å, and RMSF reveals that the protein amino acids interacting with the ligand remain within a distance of less than 1 Å. In conclusion, these findings offer a promising direction for the development of effective treatments for lung cancer