Molecular modeling study on the binding mechanisms of third-generation EGFR inhibitor Lazertinib

In recent years, in the treatment of non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) inhibitors have demonstrated ideal clinical efficacy. Unfortunately, a significant obstacle to targeted lung cancer therapy is the unavoidable emergence of acquired resistance to EGFR inhibitors through a variety of pathways during a period of medication. The third-generation EGFR inhibitor Lazertinib, which is potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing, was used to treat patients with advanced or metastatic NSCLC. Lazertinib can bind to EGFR^T790M in different conformations, identified by a 180° rotation of the pyrazole moiety, according to the X-ray co-crystal structure. A molecular modeling study integrating molecular dynamics and free energy calculation was conducted to comprehend the distinct binding manner of Lazertinib binding to EGFR and the structural need for the inhibitory activity. According to binding free energy calculations, Lazertinib has a greater binding affinity with EGFR^T790M than EGFR^WT, which is in accordance with the experimental observations. Additionally, it confirms that Lazertinib preferentially binds to EGFR^T790M with the same conformation as in EGFR^WT. The residues that made a greater contribution to the binding of Lazertinib to EGFR were identified using the per-residue energy decomposition. It is anticipated that these findings will be helpful to the rational development of new EGFR inhibitors.