Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study DOI Creative Commons
Jian Wang, Feng Yuan, Mahadevi V. Kendre

и другие.

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Апрель 28, 2025

Background The emergence of the C797S mutation in epidermal growth factor receptor (EGFR) significantly limits efficacy covalent inhibitors treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric targeting mutant EGFR using advanced silico methodologies. Methods Utilizing scaffold hopping techniques, a library compounds was generated based on known inhibitor EAI045. Virtual screening identified 44 top-scoring with strong binding affinities for EGFR. Molecular docking studies evaluated interactions, while MM-GBSA method assessed free energies. Additionally, pharmacokinetic properties were analysed Lipinski’s rule five, most promising compound, MK1, underwent molecular dynamics simulations followed by in-vitro assessment Results A total 12 heterocyclic scaffolds derived from EAI045, through virtual analysis. MK1 demonstrated highest score ΔG_bind -29.36 kcal/mol, interactions involving residues such as LYS728 MET793. MD over 100 ns confirmed stability MK1-EGFR complex, RMSD values stabilizing post-50 RMSF consistently below 3 Å. In-vitro assays validated MK1’s potent anticancer activity, showing significant cytotoxicity against lines, IC50 lower than standard comparator. Additional profiling indicated adhered Rule Five no violations, highlighting its drug-like properties. Conclusion findings highlight candidate treatment NSCLC harbouring mutation, providing valuable insights future drug development strategies

Язык: Английский

Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study DOI Creative Commons
Jian Wang, Feng Yuan, Mahadevi V. Kendre

и другие.

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Апрель 28, 2025

Background The emergence of the C797S mutation in epidermal growth factor receptor (EGFR) significantly limits efficacy covalent inhibitors treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric targeting mutant EGFR using advanced silico methodologies. Methods Utilizing scaffold hopping techniques, a library compounds was generated based on known inhibitor EAI045. Virtual screening identified 44 top-scoring with strong binding affinities for EGFR. Molecular docking studies evaluated interactions, while MM-GBSA method assessed free energies. Additionally, pharmacokinetic properties were analysed Lipinski’s rule five, most promising compound, MK1, underwent molecular dynamics simulations followed by in-vitro assessment Results A total 12 heterocyclic scaffolds derived from EAI045, through virtual analysis. MK1 demonstrated highest score ΔG_bind -29.36 kcal/mol, interactions involving residues such as LYS728 MET793. MD over 100 ns confirmed stability MK1-EGFR complex, RMSD values stabilizing post-50 RMSF consistently below 3 Å. In-vitro assays validated MK1’s potent anticancer activity, showing significant cytotoxicity against lines, IC50 lower than standard comparator. Additional profiling indicated adhered Rule Five no violations, highlighting its drug-like properties. Conclusion findings highlight candidate treatment NSCLC harbouring mutation, providing valuable insights future drug development strategies

Язык: Английский

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