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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Molecular dynamics simulations show that conformational selection governs the binding preferences of imatinib for

Alexey Aleksandrov1, Thomas Simonson

  • 1Department of Biology, Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique, 91128 Palaiseau, France.

The Journal of Biological Chemistry
|March 5, 2010
PubMed

Insights

Imatinib

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Tyrosine kinases are crucial for cell signaling, regulating processes through phosphorylation and conformational changes.
  • The cancer drug imatinib targets specific tyrosine kinases like Abl but has weaker interactions with others, such as Src.
  • Imatinib preferentially binds to the inactive 'DFG-out' conformation of Abl, distinct from Src's preferred 'DFG-in' state.

Purpose of the Study:

  • To investigate the molecular basis for imatinib's differential binding affinity to Abl and Src kinases.
  • To quantify the contributions of protein-imatinib interactions and conformational selection to binding specificity.
  • To elucidate the role of kinase conformation in drug targeting and specificity.

Main Methods:

  • Molecular dynamics simulations were employed to analyze protein-imatinib interactions in different kinase conformations.
  • Free energy calculations were used to decompose binding energy into interaction and conformational selection components.
  • Experimental binding free energy differences were utilized to deduce the contribution of conformational selection.

Main Results:

  • The direct protein-imatinib interactions (Contribution i) in the DFG-out conformation are minimal and similar between Abl and Src (0.2 ± 0.6 kcal/mol).
  • The ability of imatinib to select or induce the DFG-out conformation (Contribution ii) is the dominant factor in specificity, measuring 4.4 ± 0.9 kcal/mol.
  • Conformational selection significantly influences imatinib binding to other kinases, including c-Kit and Lck.

Conclusions:

  • Imatinib's specificity for Abl over Src is primarily driven by conformational selection, not direct binding interactions.
  • The stability difference between DFG-out and DFG-in conformations dictates imatinib's selectivity.
  • Understanding conformational selection is key for engineering targeted kinase inhibitors and advancing kinase signaling research.

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