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Deciphering the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FMS-like tyrosine kinase 3.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2024 Jul; Vol. 42 (11), pp. 5817-5826. Date of Electronic Publication: 2023 Jun 29. - Publication Year :
- 2024
-
Abstract
- FMS-like tyrosine kinase (FLT3) has become the legitimate molecular therapeutic target for acute myeloid leukemia therapy. Though FLT3 inhibitors have impact on disease progression, drug resistance induced by secondary point mutations is the primary mechanism and urgent to overcome. Herein, we sought to decipher the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FLT3. A series of molecular modeling studies, including molecular dynamics (MD) simulation, dynamic cross-correlation (DCC) analysis, binding free energy (MM-GBSA) and docking study were explored to elucidate the differential tolerance mechanisms of two inhibitors to the same mutant. The F691L mutation had relatively larger effect on gilteritinib than HM43239, which showed as the changed and fixed conformation, respectively. These observations rationalized that the binding affinity of gilteritinib decreased more than that of HM43239 in the F691L mutant.Communicated by Ramaswamy H. Sarma.
- Subjects :
- Humans
Drug Resistance, Neoplasm genetics
Protein Binding
Triazines pharmacology
Triazines chemistry
Hydrogen Bonding
Binding Sites
Thermodynamics
Pyrazines pharmacology
Pyrazines chemistry
fms-Like Tyrosine Kinase 3 genetics
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
fms-Like Tyrosine Kinase 3 chemistry
fms-Like Tyrosine Kinase 3 metabolism
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Molecular Dynamics Simulation
Molecular Docking Simulation
Mutation
Aniline Compounds pharmacology
Aniline Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 42
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 37382586
- Full Text :
- https://doi.org/10.1080/07391102.2023.2229447