Several receptor kinases (RKs) are implicated in malignant cancers that exploit RK dependent cellular growths signaling pathways. The therapeutic benefit of small molecular inhibitors of RKs have been hampered by secondary drug-resistant mutations that lowers the efficacy of the inhibitors.  We have studied molecular interactions between epidermal growth factor receptor (EGFR) and the small molecular inhibitors targeting the protein using molecular dynamics (MD) simulations. We computed the influence of a mutation (T790M) known to cause drug-resistance to the binding of the EGFR selective inhibitors. Using thermodynamic integration MD simulations, we demonstrated that the mutation (T790M) lowers the binding affinity of several reversible inhibitors of EGFR to the enzymatically active conformation of the protein. Metadynamics MD simulations of WT and mutant EGFRs in the <i>apo</i> protein show that the mutation causes a conformational equilibrium shift toward the active conformation. The binding energy penalty to the active conformation and the equilibrium shift toward the active state explain the observed dissociation constant profile of gefitinib. We also quantified the target selectivity of the EGFR inhibitors. Based on a series of metadynamics MD simulations of EGFRs bound to gefitinib, we demonstrate that EGFR bound to gefitinib favors the active over the Src/Cdk-like inactive conformations. Once the drug-resistant dual mutation (T790M/L858R) is introduced, the equilibrium shifts toward the Src/Cdk-like inactive conformation, which agrees with a recent crystallographic study that showed gefitinib interacts with the inactive conformation of the T790M/L858R dual mutant. These computational results provide fine details of the inhibitor-protein interactions, which will guide further development of the receptor kinase inhibitors.

Molecular dynamics studies of the effects of drug-resistant mutations of EGFR on inhibitor binding affinities and the drug target selectivity profiles

251st National Meeting (2016)

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