Discovery of a Potential Inhibitor Against Lung Cancer: Computational Approaches and Molecular Dynamics Study

Lung cancer, the leading cause of cancer-related deaths globally, presents a formidable challenge due to delayed diagnoses and limited treatment options, contributing to persistently low five-year survival rates. This study aimed to identify a novel inhibitor for lung cancer through an exhaustive screening process. Initial exploration of a database containing over 500,000 molecules led to an ADME-Tox study, narrowing the selection down to 20,000 molecules. Subsequent molecular docking studies, employing SP and XP methods, revealed compelling candidates. From docking results, the top 250 molecules with significantly high docking scores were examined. Only two specific molecules, L3 with a notable docking score of-11.4 and L2 scoring-10.344, exhibited exceptional binding affinities compared to the reference compound (9FX), a recognized lung cancer inhibitor. These potent compounds displayed promising drug-like properties, boasting higher molecular weights (L2: 352.41 and L3: 341.36) compared to 9FX (342.35). Additionally, they showcased similar or superior LogP values (lipophilicity) and LogS values (aqueous solubility), signifying their potential for enhanced drug-like characteristics. Molecular dynamics (MD) simulations focusing on the protein-ligand complexes involving protein 5ZMA and the ligands L2 and L3 provided crucial insights. The simulations unveiled dynamic behaviors and potential adaptive structural changes within the protein-ligand complex. Notably, specific residues, particularly ILE-267 and LYS-494, demonstrated increased flexibility, potentially serving as pivotal hotspots for effective ligand binding or allosteric interactions. Our study identifies compounds L2 and L3 as strong contenders for lung cancer treatment. We propose advancing these compounds for further research and potential clinical trials.