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Structure-kinetic relationship study of CDK8/CycC specific compounds.

Elisabeth V Schneider1, Jark Böttcher, Robert Huber

  • 1Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany. schneider@proteros.com

Proceedings of the National Academy of Sciences of the United States of America
|May 1, 2013
PubMed
Summary

This study explores the structure-kinetic relationship of cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) inhibitors. Modifying compound structures impacts binding kinetics and residence time, with hydrophobic interactions being key.

Keywords:
kinetic profilingstructure-based drug design

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Structure-activity relationships (SAR) are well-studied for drug discovery.
  • Structure-kinetic relationships (SKR), linking compound structure to binding kinetics, are less explored.
  • Understanding SKR is crucial for optimizing drug residence time.

Purpose of the Study:

  • To investigate the structure-kinetic relationship (SKR) of inhibitors targeting the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex.
  • To determine how structural modifications influence binding kinetics and residence time.
  • To identify key interactions governing the binding of small molecules to CDK8/CycC.

Main Methods:

  • Synthesis of diverse compounds with variations in scaffold and functional groups.
  • Kinetic binding assays to measure association and dissociation rates.
  • Structural analysis to correlate compound features with binding properties.

Main Results:

  • Compound structural variations significantly altered binding kinetics, shifting from fast to slow binding and improving residence time.
  • Hydrophobic interactions in the kinase front pocket had a greater impact on residence time than hinge region hydrogen bonding.
  • The DFG motif's conformation (DFG-in vs. DFG-out) showed minimal influence on binding velocity.

Conclusions:

  • Structural modifications of CDK8/CycC inhibitors can be rationally designed to modulate binding kinetics and enhance residence time.
  • Hydrophobic interactions within the front pocket are critical determinants of inhibitor residence time.
  • SKR studies provide valuable insights for developing potent and effective kinase inhibitors.