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Related Experiment Videos

Library design for fragment based screening.

Ansgar Schuffenhauer1, Simon Ruedisser, Andreas L Marzinzik

  • 1Novartis Institutes of Biomedical Research, CH-4002 Basel, Switzerland. ansgar.schuffenhauer@novartis.com

Current Topics in Medicinal Chemistry
|August 17, 2005
PubMed
Summary
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Screening small molecular fragments with high sensitivity, such as with Nuclear Magnetic Resonance (NMR) screening, yields higher hit rates for detecting ligand binding compared to traditional high-throughput screening (HTS) of larger molecules. This approach optimizes fragment libraries for drug discovery.

Area of Science:

  • Drug Discovery
  • Medicinal Chemistry
  • Biophysics

Background:

  • Hann's model suggests small, low-complexity molecular fragments detected with high sensitivity increase the probability of binding to target proteins.
  • Traditional high-throughput screening (HTS) often uses lower sensitivity for full-sized ligands, potentially missing fragment-level interactions.
  • Fragment-based lead discovery (FBLD) is a key strategy in modern drug development.

Purpose of the Study:

  • To validate Hann's model by comparing hit rates of fragment screening versus HTS.
  • To evaluate the effectiveness of generic fragment libraries in drug discovery.
  • To optimize fragment libraries for improved chemical tractability and follow-up synthesis.

Main Methods:

  • Comparative analysis of Novartis's HTS summary data with NMR screening results from generic fragment libraries.

Related Experiment Videos

  • Evaluation of hit rates based on IC(50) thresholds in micromolar (HTS) and millimolar (NMR) ranges.
  • Survey of literature case studies on fragment-based lead discovery.

    • Main Results:

    • NMR screening of fragments demonstrated significantly higher hit rates (≥3%) compared to HTS (0.001%-0.151%) for detecting ligand binding.
    • Generic fragment libraries are a common source for initial hits in FBLD, appearing in approximately half of reported cases.
    • Optimization of fragment libraries focused on chemical tractability, masking functional groups for easier subsequent modification.

    Conclusions:

    • High-sensitivity screening of small molecular fragments, particularly using NMR, is more effective for identifying initial ligand binding events than traditional HTS.
    • Generic fragment libraries are valuable starting points, and their chemical tractability can be enhanced through strategic masking of functional groups.
    • Further research is needed to fully conclude on NMR screening's potential due to limited experience and non-identical target sets in the comparison.