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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Published on: December 7, 2014

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Insight on mutation-induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics

Mu-Yang He1, Wei-Kang Li1, Jens Meiler2

  • 1Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun, People's Republic of China.

Biopolymers
|January 22, 2019
PubMed

Insights

Ceritinib resistance in ALK cancers arises from mutations like G1123S and F1174C. These changes alter the drug

Area of Science:

  • Oncology
  • Molecular Biology
  • Biophysics

Background:

  • Ceritinib is a next-generation inhibitor targeting anaplastic lymphoma kinase (ALK) for ALK-associated cancers.
  • Acquired resistance mutations diminish ceritinib's therapeutic effectiveness, despite known mutagenesis data.
  • Structural reasons for reduced ceritinib binding in resistant mutants remain unclear.

Purpose of the Study:

  • To investigate the structural determinants of ceritinib resistance mutations G1123S and F1174C.
  • To elucidate the molecular mechanisms underlying reduced ceritinib binding affinity.

Main Methods:

  • Utilized molecular dynamics (MD) simulations to analyze the impact of G1123S and F1174C mutations.
  • Focused on conformational changes within the ATP-binding pocket of ALK.

Main Results:

  • MD simulations indicate that G1123S and F1174C mutations allosterically affect the ATP-binding pocket configuration.
  • Identified a key hydrophobic cluster connecting the P-loop and αC-helix, crucial for ATP-binding pocket stability.
  • These mutations induce conformational changes in the P-loop, leading to decreased ceritinib affinity.

Conclusions:

  • The G1123S and F1174C mutations confer ceritinib resistance by altering the ALK ATP-binding pocket structure.
  • Conformational changes in the P-loop are a key mechanism driving reduced drug binding and resistance.
  • Understanding these structural changes can inform strategies to overcome ceritinib resistance.
Keywords:
ALKNSCLCceritinibdrug-resistance mutationsintermolecular interaction

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