Molecular Diversity

, Volume 17, Issue 2, pp 319–335 | Cite as

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

  • Andrew S. Bell
  • Joseph Bradley
  • Jeremy R. Everett
  • Michelle Knight
  • Jens Loesel
  • John Mathias
  • David McLoughlin
  • James Mills
  • Robert E. Sharp
  • Christine Williams
  • Terence P. Wood
Full-Length Paper

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.

Keywords

Rule of 40 (Ro40) High throughput screening (HTS) Plate based Diversity Subset Screening file 

Abbreviations and definitions

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

Supplementary material

11030_2013_9438_MOESM1_ESM.docx (431 kb)
Supplementary material 1 (docx 430 KB)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Andrew S. Bell
    • 1
    • 2
  • Joseph Bradley
    • 1
    • 3
  • Jeremy R. Everett
    • 1
    • 4
  • Michelle Knight
    • 1
    • 5
  • Jens Loesel
    • 1
    • 6
  • John Mathias
    • 1
    • 7
  • David McLoughlin
    • 1
    • 8
  • James Mills
    • 1
    • 9
  • Robert E. Sharp
    • 10
    • 11
  • Christine Williams
    • 1
    • 12
  • Terence P. Wood
    • 1
    • 13
  1. 1.Pfizer Worldwide Research and DevelopmentSandwich, KentUK
  2. 2.Imperial CollegeLondonUK
  3. 3.Scitegrity LtdSandwich, KentUK
  4. 4.University of GreenwichChatham Maritime, KentUK
  5. 5.Canterbury Christchurch UniversityCanterbury, KentUK
  6. 6.Peter Fisk Associates LimitedCanterbury, KentUK
  7. 7.Pfizer ResearchCambridgeUSA
  8. 8.Eli Lilly & CompanyIndianapolisUSA
  9. 9.SandexisCanterbury, KentUK
  10. 10.Pfizer Worldwide Research & Development GrotonUSA
  11. 11.Intrexon CorporationSan CarlosUSA
  12. 12.Kent and Canterbury HospitalCanterbury, KentUK
  13. 13.TP & AAW ConsultancyCliftonville, KentUK

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