Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2

Area of Science:

• Oncology
• Molecular Biology
• Computational Chemistry

Background:

• Epidermal Growth Factor Receptor (EGFR) and Human Epidermal growth factor Receptor 2 (HER2) overexpression is common in various human cancers.
• Dual inhibitors targeting EGFR/HER2 represent a key anti-cancer therapeutic strategy.
• Lapatinib derivatives have been synthesized, with compound 2i showing notable inhibitory activity against EGFR/HER2-overexpressing cancer cells.

Purpose of the Study:

• To investigate the structural and energetic factors governing the molecular recognition of lapatinib derivative 2i by EGFR/HER2.
• To compare the binding affinity of compound 2i with lapatinib across different EGFR/HER2 conformational states.
• To elucidate the impact of compound 2i binding on the conformational dynamics of EGFR/HER2.

Main Methods:

• Molecular Dynamics (MD) simulations were employed to model inactive EGFR/HER2-ligand complexes.
• The MMPB(GB)SA approach was utilized to calculate binding free energies.
• Principal Component Analysis (PCA) was performed to analyze conformational mobility changes upon ligand binding.

Main Results:

• Compound 2i exhibited increased binding affinity for inactive EGFR/HER2 compared to lapatinib, aligning with experimental findings.
• Both lapatinib and compound 2i demonstrated stronger binding to the inactive HER2 state than the intermediate active-inactive state.
• Binding of compound 2i to EGFR/HER2 resulted in reduced conformational mobility, potentially contributing to its enhanced affinity.

Conclusions:

• Slight structural modifications in lapatinib, as seen in compound 2i, can significantly enhance binding affinity for inactive EGFR/HER2.
• The enhanced affinity of compound 2i is linked to a reduction in receptor conformational flexibility.
• Compound 2i represents a promising candidate for further development as a dual EGFR/HER2 inhibitor in cancer therapy.