Fragment Screening

 

Fragment-based drug design has become an increasingly popular platform for the identification of lead candidates in drug discovery programs. The detection and characterization of fragment binding events is facilitated by sensitive biophysical technologies capable of detecting low affinity interactions of low molecular weight compounds. Over the last decade approaches such as nuclear magnetic resonance (NMR), X-ray crystallography, differential scanning fluorimetry (DSF), and surface plasmon resonance (SPR) have become core technologies in many pharma and biotech settings for the identification of these low-affinity fragment compounds. SPR-based biosensors such as the Pioneer FE have sufficient sensitivity and throughput to provide complete fragment screens on libraries of several thousand compounds in just a few weeks per target.

The Pioneer FE system is well suited for fragment screening due to its flow cell design, gradient injection capabilities (OneStep® and NeXtStep) and two microplate sample racks. It provides significant time and reagent saving compared to conventional fragment screening.

In fragment screening projects, Pioneer FE can:

  • Determine kinetics (ka, kd) and affinity (KD) constants from the primary fragment screen with OneStep
  • Test up to 768 fragments in 24 hrs with OneStep and eliminate secondary screening
  • Test up to two therapeutic targets versus a fragment library
  • Test fragments for competition mechanism and determine kinetics (ka, kd) and affinity (KD) in the presence of a competitor molecule
  • Accurately select hits from primary screen data using a novel normalization and selection algorithm developed in collaboration with industry leaders at GSK and Genentech
  • Provide significant time and reagent saving compared to conventional SPR-based fragment screening

The conventional fragment screening workflow has been significantly improved by integrating the Pioneer FE and its breakthrough diSPR® technologies, OneStep and NeXtStep.

Conventional SPR-based fragment screening workflow

Figure 1: A) Conventional SPR-based fragment screening workflow to deliver characterized fragment hits to Medicinal Chemistry groups. B) diSPR optimized fragment screening workflow to deliver fully characterized fragment hits to Medicinal Chemistry groups.

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