Daidzein derivatives as potential inhibitors of mutant EGFR in non-small cell lung cancer: A computational study supported by molecular docking, DFT, molecular dynamics simulations, and MM/PBSA techniques.

BACKGROUND

Lung cancer (LC) continues to be the foremost cause of cancer-related deaths worldwide. However, resistance to epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) poses serious challenges to current treatments, and there is a need to identify small molecules to counteract this resistance.

OBJECTIVE

This study aims to identify novel small molecules targeting a mutant EGFR kinase construct containing (L858R/T790M/V948R) using computational approaches.

METHODS

An integrated computational workflow, i.e., Lipinski's Rule of five, ADMET profiling, density functional theory, molecular docking, and molecular dynamics (MD) simulation, was used to screen potential molecules from an initial library of 88 compounds from the PubChem database.

RESULTS AND DISCUSSION: Molecular docking studies have shown that daidzein compounds have more favorable docking scores (-9.84 to -8.98 kcal/mol) than the co-crystallized ligand (-7.60 kcal/mol). The molecular docking results were further examined using MD simulations and post-MD analysis. These compounds showed a variable predicted ADMET profile, with compound 1 displaying the most favorable profile. Electrostatic potential and frontier molecular orbitals have been calculated to explore the potential reactive sites and molecular stability. Moreover, based on MM/PBSA analysis, the binding free energy for compound 1 is -194.07 kJ/mol, as compared to the reference compound -71.13 kJ/mol, thereby demonstrating its enhanced binding affinity towards the target protein.

CONCLUSIONS AND FUTURE PROSPECTS: These findings support further investigation of daidzein derivatives as potential inhibitors of mutant EGFR in NSCLC, whereas compound 1 is a putative lead candidate requiring rigorous experimental validation.