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Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies.

Author information

Affiliations

  • 1. Novartis Institutes for BioMedical Research, Cambridge, MA, USA Current address: Merck, Boston, MA, USA.
      Authors
    • Kutchukian PS 1
    (1 author)
  • 2. Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
      Authors
    • Wassermann AM 2
    • Wright SK 2
    • Jacob J 2
    (3 authors)
  • 3. Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
      Authors
    • Lindvall MK 3
    (1 author)
  • 4. Novartis Institutes for BioMedical Research, Basel, Switzerland.
      Authors
    • Ottl J 4
    • Scheufler C 4
    • Marzinzik A 4
    (3 authors)
  • 5. Novartis Institutes for BioMedical Research, Cambridge, MA, USA Current address: Blueprint Medicines, Cambridge, MA, USA.
      Authors
    • Brooijmans N 5
    (1 author)
    • Show all (6)

ORCIDs linked to this article

Journal of Biomolecular Screening, 30 Dec 2014, 20(5):588-596
https://doi.org/10.1177/1087057114565080 PMID: 25550355 

Abstract 

A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment "hits." However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits.

Full text links 

Read article at publisher's site: https://doi.org/10.1177/1087057114565080

Read article for free, from open access legal sources, via Unpaywall: https://journals.sagepub.com/doi/pdf/10.1177/1087057114565080Unpaywall

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