Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study
BackgroundThe emergence of the C797S mutation in the epidermal growth factor receptor (EGFR) significantly limits the efficacy of covalent inhibitors in treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric inhibitors targeting the C797S mutant EGFR us...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1590779/full |
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| author | Jian Wang Feiyang Yuan Mahadevi Kendre Zhijin He Shaowei Dong Abhinandan Patil Kausing Padvi |
| author_facet | Jian Wang Feiyang Yuan Mahadevi Kendre Zhijin He Shaowei Dong Abhinandan Patil Kausing Padvi |
| author_sort | Jian Wang |
| collection | DOAJ |
| description | BackgroundThe emergence of the C797S mutation in the epidermal growth factor receptor (EGFR) significantly limits the efficacy of covalent inhibitors in treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric inhibitors targeting the C797S mutant EGFR using advanced in silico methodologies.MethodsUtilizing scaffold hopping techniques, a library of compounds was generated based on the known allosteric inhibitor EAI045. Virtual screening identified 44 top-scoring compounds with strong binding affinities for the C797S mutant EGFR. Molecular docking studies evaluated binding interactions, while the MM-GBSA method assessed binding free energies. Additionally, pharmacokinetic properties were analysed using Lipinski’s rule of five, and the most promising compound, MK1, underwent molecular dynamics simulations followed by in-vitro assessmentResultsA total of 12 heterocyclic scaffolds were derived from EAI045, and 44 top-scoring compounds were identified through virtual screening and MM-GBSA analysis. MK1 demonstrated the highest docking score and a ΔG_bind of -29.36 kcal/mol, with strong interactions involving residues such as LYS728 and MET793. MD simulations over 100 ns confirmed the stability of the MK1-EGFR complex, with RMSD values stabilizing post-50 ns and RMSF values consistently below 3 Å. In-vitro assays validated MK1’s potent anticancer activity, showing significant cytotoxicity against C797S mutant cell lines, with IC50 values lower than the standard comparator. Additional pharmacokinetic profiling indicated MK1 adhered to Lipinski’s Rule of Five with no violations, highlighting its drug-like properties.ConclusionThe findings highlight MK1 as a promising candidate for the treatment of NSCLC harbouring the C797S mutation, providing valuable insights for future drug design and development strategies targeting mutant EGFR. |
| format | Article |
| id | doaj-art-36f19460454e45cf863e5013c3e79d5c |
| institution | OA Journals |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj-art-36f19460454e45cf863e5013c3e79d5c2025-08-20T02:20:06ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-04-011510.3389/fonc.2025.15907791590779Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro studyJian Wang0Feiyang Yuan1Mahadevi Kendre2Zhijin He3Shaowei Dong4Abhinandan Patil5Kausing Padvi6Department of Thoracic Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, ChinaDepartment of Thoracic Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, ChinaDepartment of Chemical Technology, Dr Babasaheb Ambedkar Marathwada University, Chhatrapati Sambhajinagar, IndiaDepartment of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United StatesDepartment Paediatric Research, Shenzhen Children’s Hospital, Shenzhen, ChinaDepartment of Pharmacy, DY Patil University, Kolhapur, Maharashtra, IndiaDepartment of Chemical Technology, Dr Babasaheb Ambedkar Marathwada University, Chhatrapati Sambhajinagar, IndiaBackgroundThe emergence of the C797S mutation in the epidermal growth factor receptor (EGFR) significantly limits the efficacy of covalent inhibitors in treating non-small cell lung cancer (NSCLC). This study aimed to design and evaluate novel allosteric inhibitors targeting the C797S mutant EGFR using advanced in silico methodologies.MethodsUtilizing scaffold hopping techniques, a library of compounds was generated based on the known allosteric inhibitor EAI045. Virtual screening identified 44 top-scoring compounds with strong binding affinities for the C797S mutant EGFR. Molecular docking studies evaluated binding interactions, while the MM-GBSA method assessed binding free energies. Additionally, pharmacokinetic properties were analysed using Lipinski’s rule of five, and the most promising compound, MK1, underwent molecular dynamics simulations followed by in-vitro assessmentResultsA total of 12 heterocyclic scaffolds were derived from EAI045, and 44 top-scoring compounds were identified through virtual screening and MM-GBSA analysis. MK1 demonstrated the highest docking score and a ΔG_bind of -29.36 kcal/mol, with strong interactions involving residues such as LYS728 and MET793. MD simulations over 100 ns confirmed the stability of the MK1-EGFR complex, with RMSD values stabilizing post-50 ns and RMSF values consistently below 3 Å. In-vitro assays validated MK1’s potent anticancer activity, showing significant cytotoxicity against C797S mutant cell lines, with IC50 values lower than the standard comparator. Additional pharmacokinetic profiling indicated MK1 adhered to Lipinski’s Rule of Five with no violations, highlighting its drug-like properties.ConclusionThe findings highlight MK1 as a promising candidate for the treatment of NSCLC harbouring the C797S mutation, providing valuable insights for future drug design and development strategies targeting mutant EGFR.https://www.frontiersin.org/articles/10.3389/fonc.2025.1590779/fullallosteric inhibitorsC797S mutant EGFRnon-small cell lung cancerdrug designin-vitro assessment |
| spellingShingle | Jian Wang Feiyang Yuan Mahadevi Kendre Zhijin He Shaowei Dong Abhinandan Patil Kausing Padvi Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study Frontiers in Oncology allosteric inhibitors C797S mutant EGFR non-small cell lung cancer drug design in-vitro assessment |
| title | Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study |
| title_full | Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study |
| title_fullStr | Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study |
| title_full_unstemmed | Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study |
| title_short | Rational design of allosteric inhibitors targeting C797S mutant EGFR in NSCLC: an integrative in silico and in-vitro study |
| title_sort | rational design of allosteric inhibitors targeting c797s mutant egfr in nsclc an integrative in silico and in vitro study |
| topic | allosteric inhibitors C797S mutant EGFR non-small cell lung cancer drug design in-vitro assessment |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1590779/full |
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