title: Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files.
abstract: High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|Imperial College, London, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|Scitegrity Ltd, Discovery Park, Sandwich, Kent, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bradley
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK. j.r.everett@greenwich.ac.uk.|University of Greenwich, Chatham Maritime, Kent, UK. j.r.everett@greenwich.ac.uk.
authors.forename: Jeremy R
authors.identifier: http://orcid.org/0000-0003-1550-4482
authors.initials: JR
authors.lastname: Everett
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|JL Consulting, Deal, Kent, UK.
authors.forename: Jens
authors.initials: J
authors.lastname: Loesel
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|Eli Lilly & Company, Indianapolis, IN, USA.
authors.forename: David
authors.initials: D
authors.lastname: McLoughlin
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|Sandexis Medicinal Chemistry Ltd, Canterbury, Kent, UK.
authors.forename: James
authors.initials: J
authors.lastname: Mills
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Peakman
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT, USA.|RES Consulting, San Francisco Bay, CA, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sharp
authors.affiliation: Pfizer Worldwide Research & Development, Sandwich, Kent, UK.|Ipsen, Slough, Berkshire, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Williams
authors.affiliation: Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Hongyao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods* / Q000592:standards; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays / Q000379:methods* / Q000592:standards; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries
keywords: 2nd Generation; Diversity; High-throughput screening (HTS); Lead discovery; Plate-based; Ro40; Rule of 40; Screening file; Subset