Journal
MOLECULES
Volume 27, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/molecules27123844
Keywords
EGFR rare mutants; EGFR complex mutations; molecular dynamics simulation; steered molecular dynamics simulation; Gefitinib (IRE)
Funding
- Nanjing Agricultural University [680804014]
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This study explores the molecular determinants of different responses to Gefitinib by EGFR mutants and finds that interactions between residues and introduced hydrogen bonds contribute to the stability of the helical structure. Additionally, it is discovered that IRE exhibits a stronger binding affinity to EGFR(G719S/L858R) mutant.
Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed understanding of the molecular basis for multiple EGFR mutants exhibiting diverse responses to inhibitors is of critical importance for related drug development. Herein, we explored the molecular determinants contributing to the distinct responses of EGFR with a single rare mutation (G719S) or combined mutations (G719S/L858R and G719S/l861Q) to Gefitinib (IRE). Our results indicated that interactions, formed within the tetrad of residues S768 (in the alpha C-helix), D770 (in the alpha C-beta 4 loop), Y827 (in the alpha E-helix), and R831 (in the catalytic loop), play an important role in the stability of alpha C-helix and the maintenance of K745-E762 salt bridge in the absence of IRE, which are weakened in the EGFR(G719S) system and enhanced in the EGFR(G719S/L858R) system upon IRE binding. Besides, the introduced hydrogen bonds by the co-occurring mutation partner also contribute to the stability of alpha C-helix. The work done for inhibitor dissociation suggests that IRE exhibits a stronger binding affinity to EGFR(G719S/L858R) mutant. Together, these findings provide a deeper understanding of minor mutations, which is essential for drug development targeting EGFR with less common mutations.
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