Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 30, Pages 10911-10916Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1410933111
Keywords
chemical diversity; biological performance diversity; biological activity; chemical similarity
Categories
Funding
- National Institutes of Health as part of the Molecular Libraries Probe Production Centers Network program [U54 HG005032]
- Library of Integrated Network-based Cellular Signatures program [U54 HG006093]
- large-scale gene expression analysis of cellular states
- National Institute of General Medical Sciences as part of the Center of Excellence for Chemical Methodology and Library Development [P50-GM069721]
- National Science Foundation [CAREER DBI 1148823]
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1148823] Funding Source: National Science Foundation
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High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.
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