Computational biophysical characterization of the effect of gatekeeper mutations on the binding of ponatinib to the FGFR kinase.
Arch Biochem Biophys
; 758: 110070, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38909834
ABSTRACT
Fibroblast Growth Factor Receptor (FGFR) is connected to numerous downstream signalling cascades regulating cellular behavior. Any dysregulation leads to a plethora of illnesses, including cancer. Therapeutics are available, but drug resistance driven by gatekeeper mutation impedes the treatment. Ponatinib is an FDA-approved drug against BCR-ABL kinase and has shown effective results against FGFR-mediated carcinogenesis. Herein, we undertake molecular dynamics simulation-based analysis on ponatinib against all the FGFR isoforms having Val to Met gatekeeper mutations. The results suggest that ponatinib is a potent and selective inhibitor for FGFR1, FGFR2, and FGFR4 gatekeeper mutations. The extensive electrostatic and van der Waals interaction network accounts for its high potency. The FGFR3_VM mutation has shown resistance towards ponatinib, which is supported by their lesser binding affinity than wild-type complexes. The disengaged molecular brake and engaged hydrophobic spine were believed to be the driving factors for weak protein-ligand interaction. Taken together, the inhibitory and structural characteristics exhibited by ponatinib may aid in thwarting resistance based on Val-to-Met gatekeeper mutations at an earlier stage of treatment and advance the design and development of other inhibitors targeted at FGFRs harboring gatekeeper mutations.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Unión Proteica
/
Piridazinas
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Simulación de Dinámica Molecular
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Imidazoles
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Mutación
Límite:
Humans
Idioma:
En
Revista:
Arch Biochem Biophys
Año:
2024
Tipo del documento:
Article
País de afiliación:
India