Mechanism of Drug Efficacy Within the EGF Receptor Revealed by Microsecond Molecular Dynamics Simulation

Abstract

The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non-small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without.

Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase

“…Therefore, active conformers share one direction of motion mainly represented by the lowest frequency normal modes. This is in agreement with previous results obtained by Coveney and coworker . using MD and PCA, that shows that the first PCA mode distinguish between active and inactive states.…”

“…Local rearrangements of the αG helix have been previously related to the conformational change of c‐Src kinase associated to ligand binding . Besides, a relative suppression of active loop deformations also characterizes modes and respect to motions of the corresponding modes of inactive conformations, in agreement with previous MD results that reveal a relatively more rigid alpha‐C helix and active loop in the active than inactive states of wild‐type and active EGFR mutants . For the sake of comparison, we also show shows the corresponding modes for inactive conformers.…”

“…Besides, the intrinsic disorder of EGFR kinase domain has been shown to play a significant role in the EGFR dimerization . Differences between active and inactive states have been also studied using MD followed by principal component analysis (PCA), finding that EGFR is more flexible in the active state than in the inactive state. Other MD studies have been centered on the analysis of SASs on the relative stability of the active versus the inactive state, and also on the conformational transition between active and inactive conformers …”

Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase

“…In the case of gefitinib, its selectivity for the mutant might be the consequence of increased affinity of the drug, which binds to an active-like conformation, combined with decreased affinity of ATP (21,22). However, the conformational selectivity of EGFR inhibitors has been recently questioned, when erlotinib was found to also bind to the inactive EGFR CD conformation (23).…”

From base pair to bedside: molecular simulation and the translation of genomics to personalized medicine

“…Two possible reasons have been proposed for different drug sensitivities of wild‐type and mutant EGFRs: mutations influence the relative strengths of inhibitor‐ and ATP‐binding,110 and the shifting of the conformational ensemble to one less preferable for drug binding 109. Recently, the use of the Anton,111 a special‐purpose massively parallel supercomputer, has allowed simulations to sample on substantially longer timescale (∼10 milliseconds) in order to address the large‐scale conformational flexibility of EGFR 112. This generates an ensemble of conformational states of which the kinase inhibitor Gefitinib is preferentially bound over ATP when EGFR harbors the L858R mutation 112.…”