Recent development in small molecular organic compounds inhibiting kinase activity of epidermal growth factor receptor (EGFR) has shown promises in non-small cell lung cancer (NSCLC) and other malignant tumors. Biochemical and clinical evidences suggested several point mutations modulate patient's response to the inhibitors targeting enzymatically active state of the protein. Cocrystallization studies have revealed invaluable structural insights, yet subtle changes in binding affinity induced by the mutations ask further insights. We have studied detailed interaction between EGFR kinase domain and its type-1 inhibitors using molecular dynamics (MD) simulation technique. First we examined how a point mutation in the drug binding site (T790M) weakens binding affinity of gefitinib . A series of thermodynamic integration (TI) and metadynamics simulations demonstrated molecular origin of steric hindrance induced by the mutation. Second, we studied the role of another point mutation (L858R) which enhances the efficacy of type-1 inhibitors. A combination of long-time MD and TI simulations showed L858R mutation stabilizes DFG-motif which has critical role in the stability of active state of the enzyme, and also facilitates binding of the compound by reducing unfavorable electrostatic interaction . These results provided detailed explanations of the drug-target interaction and clues for further development of anti-cancer therapeutic agents.

How point mutations modulate binding affinity of EGFR selective inhibitors

248th National Meeting (2014)

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