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Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file

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Abstract

The screening files of many large companies, including Pfizer, have grown considerably due to internal chemistry efforts, company mergers and acquisitions, external contracted synthesis, or compound purchase schemes. In order to screen the targets of interest in a cost-effective fashion, we devised an easy-to-assemble, plate-based diversity subset (PBDS) that represents almost the entire computed chemical space of the screening file whilst comprising only a fraction of the plates in the collection. In order to create this file, we developed new design principles for the quality assessment of screening plates: the Rule of 40 (Ro40) and a plate selection process that insured excellent coverage of both library chemistry and legacy chemistry space. This paper describes the rationale, design, construction, and performance of the PBDS, that has evolved into the standard paradigm for singleton (one compound per well) high-throughput screening in Pfizer since its introduction in 2006.

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Abbreviations

ECFP4:

SciTegic/Accelrys’ level 4 extended connectivity fingerprints

FE:

File enrichment

GDRS:

Global diverse representative subset

HTS:

High throughput screening

Legacy compound:

A molecule synthesised as a singleton or in a small group of \(\le \) 10 compounds using methods such as stem reaction blocks [46]

Library compound:

A molecule synthesised by large scale (10–100s or even 1,000s of compounds) parallel chemistry methods

PBDS:

Plate-based diversity subset

PMC:

Parallel medicinal chemistry

SAR:

Structure–activity relationships

Screening file:

The entire set of compounds in an organisation’s high throughput screening collection

Screening subset:

A screening collection produced by selecting compounds or plates from the entire screening file using either targeted or diversity approaches

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Acknowledgments

We gratefully acknowledge contributions made to this work from the following Pfizer staff in Research and Research Informatics: Alexander Alex, Francois Bertelli, Mark Gardner, Katrina Gore, Marcel De Groot, Willem Van Hoorn, Travis Mathewson, Bruce Posner, Steve Street, Tony Wood and Siew Kuen Yeap.

Author information

Author notes

  1. Andrew S. Bell

    Present address: Imperial College, London, UK

  2. Joseph Bradley

    Present address: Scitegrity Ltd, Discovery Park, Sandwich, Kent, UK

  3. Jeremy R. Everett

    Present address: University of Greenwich, Chatham Maritime, Kent, UK

  4. Michelle Knight

    Present address: Canterbury Christchurch University, Canterbury, Kent, UK

  5. Jens Loesel

    Present address: Peter Fisk Associates Limited, Canterbury, Kent, UK

  6. John Mathias

    Present address: Pfizer Research, Cambridge, MA, USA

  7. David McLoughlin

    Present address: Eli Lilly & Company, Indianapolis, IN, USA

  8. James Mills

    Present address: Sandexis, Canterbury, Kent, UK

  9. Robert E. Sharp

    Present address: Intrexon Corporation, San Carlos, CA, USA

  10. Christine Williams

    Present address: Kent and Canterbury Hospital, Canterbury, Kent, UK

  11. Terence P. Wood

    Present address: TP & AAW Consultancy, Cliftonville, Kent, UK

Authors and Affiliations

  1. Pfizer Worldwide Research and Development, Sandwich, Kent, UK

    Andrew S. Bell, Joseph Bradley, Jeremy R. Everett, Michelle Knight, Jens Loesel, John Mathias, David McLoughlin, James Mills, Christine Williams & Terence P. Wood

  2. Pfizer Worldwide Research & Development, Groton, CT, USA

    Robert E. Sharp

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Corresponding authors

Correspondence to Jeremy R. Everett or Jens Loesel.

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Bell, A.S., Bradley, J., Everett, J.R. et al. Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file. Mol Divers 17, 319–335 (2013). https://doi.org/10.1007/s11030-013-9438-x

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  • DOI: https://doi.org/10.1007/s11030-013-9438-x

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