title: Small-Molecule Library Subset Screening as an Aid for Accelerating Lead Identification.
abstract: Several small-compound library subsets (14,000 to 56,000) have been established to complement screening of a larger Genentech corporate library (~1,300,000). Two validation sets (~1% of the total library) containing compounds representative of the main library were chosen by selection of plates or individual compounds. Use of these subsets guided selection of assay configuration, validated assay reproducibility, and provided estimates of hit rates expected from our full library. A larger diversity subset representing the scaffold diversity of the full library (3.4% of the total) was designed for screening more challenging targets with limited reagent availability or low-throughput assays. Retrospective analysis of this subset showed hit rates similar to those of the main library while recovering a higher proportion of hit scaffolds. Finally, a property-restricted diversity set called the "in-between library" was established to identify ligand-efficient compounds of molecular size between those typically found in fragment and high-throughput screening libraries. It was screened at fivefold higher concentrations than the main library to facilitate identification of less potent yet ligand-efficient compounds. Taken together, this work underscores the value of generating multiple purpose-focused, diversity-based library subsets that are designed using computational approaches coupled with internal screening data analyses to accelerate the lead discovery process.
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Maureen H
authors: MH
authors: Beresini
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Yichin
authors: Y
authors: Liu
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Timothy D
authors: TD
authors: Dawes
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Kevin R
authors: KR
authors: Clark
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Linda
authors: L
authors: Orren
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Stephen
authors: S
authors: Schmidt
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Rebecca
authors: R
authors: Turincio
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Steven W
authors: SW
authors: Jones
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Richard A
authors: RA
authors: Rodriguez
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Peter
authors: P
authors: Thana
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Daniel
authors: D
authors: Hascall
authors: Department of Biochemical & Cellular Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors: Daniel P
authors: DP
authors: Gross
authors: Department of Discovery Chemistry, Genentech Inc, South San Francisco, CA, USA beresini@gene.com skelly@gene.com.
authors: Nicholas J
authors: NJ
authors: Skelton
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D020128:Inhibitory Concentration 50; D008024:Ligands; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries
keywords: compound library; high-throughput screening; library subset; molecular diversity