title: 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.
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, WC1H 0AJ, United Kingdom.
authors.forename: Shunzhou
authors.initials: S
authors.lastname: Wan
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004795:Enzyme Stability / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077156:Gefitinib; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D025341:Principal Component Analysis; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D000077156:Gefitinib