Interrogating Ligand: Target Interactions Using Back-Scattering Interferometry Yields Mechanistic Insight and Aids in Compound Prioritization

Layton Harris Smith, PhD
Wednesday, February 3, 2016
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Chapters

  • Introduction
  • Cardioprotective effects of apelin
  • Apelin and its receptor (APJ)
  • Apelin maintains cardiac function in a mouse model of heart failure
  • uHTS for novel small molecule APJ agonists
  • APJ agonist uHTS stats
  • APJ Agonist Chemistry Summary
  • SBI-’692 is a potent small molecule agonist of APJ
  • SBI-’692 increases hiPSC-derived cardiac myocyte contractility
  • SBI-’692 increases contractility but not heart rate in vivo
  • APJ Agonists do not recapitulate
  • SBI-’692 is selective for APJ
  • Lead compounds compete for Ap13 binding
  • Back-scattering interferometry
  • Direct Ap13:APJ interaction as measured by BSI
  • Label-free ligand : target interaction analysis by BSI
  • Ligand mechanistic discrimination
  • Ap13 exhibits classic 2-state binding mode
  • GTPP(CH3)P reveals unique binding mode of SBI-692
  • Revised APJ agonist
  • Summary
  • Acknowledgments
  • Thank You
 

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