Mechanistic insights into the allosteric inhibition of EGFR by dibenzodiazepinone DDC4002: A molecular dynamics, binding free energy, conformational motions and thermodynamic landscape approach

The epidermal growth factor receptor (EGFR) is a well-established target in the treatment of non-small cell lung cancer (NSCLC). Although third-generation EGFR inhibitors such as Osimertinib have shown clinical success against the T790M mutation, they lose effectiveness against the C797S mutation. As all approved EGFR inhibitors are ATP-competitive, there is a growing need for alternative approaches, such as allosteric inhibition. DDC4002, a dibenzodiazepinone analog of EAI045, demonstrates potent activity against EGFR L858R/T790M and L858R/T790M/C797S mutants while sparing wild-type EGFR. In this study, we employed molecular dynamics simulations using Schrodinger Desmond, MM-GBSA free energy calculations, and principal component analysis (PCA) to explore the dynamic behavior and binding mechanism of DDC4002 with mutant EGFR. The results revealed that DDC4002 stabilizes the inactive conformation of EGFR and maintains strong binding interactions within the allosteric pocket. The free energy landscape and motion analyses further supported the conformational restriction induced by the inhibitor. These insights provide a structural and energetic rationale for the development of next-generation allosteric EGFR inhibitors to overcome drug resistance in NSCLC.