Elucidating the potential of EGFR mutated NSCLC and identifying its multitargeted inhibitors

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Lung cancer is a leading cause of cancer mortality worldwide.
• Epidermal growth factor receptor (EGFR) gene mutations are common in non-small cell lung cancer (NSCLC).
• Curcumin and CB[2]UN possess medicinal properties relevant to drug delivery.

Purpose of the Study:

• To investigate the efficacy of curcumin and CB[2]UN in controlling EGFR-mutant NSCLC using a dodecagonal computational approach.
• To assess the binding affinity and stability of curcumin and CB[2]UN with EGFR-mutant NSCLC proteins.

Main Methods:

• Molecular docking studies were performed to evaluate ligand-protein interactions.
• Molecular dynamics simulations (50 ns) assessed kinetic stability using RMSD, RMSF, Rg, and SASA.
• MMPBSA/MMGBSA and KDeep calculations determined thermodynamic stability and absolute binding affinities.

Main Results:

• Curcumin and CB[2]UN exhibited strong binding affinities to EGFR-mutant NSCLC proteins (2ITX and 2ITV, respectively).
• Molecular dynamics simulations indicated kinetic stability of the protein-ligand complexes.
• Thermodynamic analysis confirmed the stability, with KDeep calculations showing significant binding energies (-6.13 kcal/mol for 2ITX-CUR and -5.26 kcal/mol for 2ITV-CB[2]UN).

Conclusions:

• The dodecagonal computational strategy suggests that 2ITX-CUR and 2ITV-CB[2]UN complexes possess high binding affinities and excellent stability.
• Curcumin and CB[2]UN show promise as potential therapeutic agents for EGFR-mutant NSCLC.