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J Biomol Screen DOI:10.1177/1087057113520226

Connecting Small Molecules with Similar Assay Performance Profiles Leads to New Biological Hypotheses.

Publication TypeJournal Article
Year of Publication2014
AuthorsDančík, V, Carrel, H, Bodycombe, NE, Seiler, KPetri, Fomina-Yadlin, D, Kubicek, ST, Hartwell, K, Shamji, AF, Wagner, BK, Clemons, PA
JournalJ Biomol Screen
Date Published2014 Jun
KeywordsAlgorithms, Animals, Bayes Theorem, Cell Line, Tumor, Cluster Analysis, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Membrane Potential, Mitochondrial, Mice, Models, Molecular, Phenotype, Reproducibility of Results, Small Molecule Libraries

High-throughput screening allows rapid identification of new candidate compounds for biological probe or drug development. Here, we describe a principled method to generate "assay performance profiles" for individual compounds that can serve as a basis for similarity searches and cluster analyses. Our method overcomes three challenges associated with generating robust assay performance profiles: (1) we transform data, allowing us to build profiles from assays having diverse dynamic ranges and variability; (2) we apply appropriate mathematical principles to handle missing data; and (3) we mitigate the fact that loss-of-signal assay measurements may not distinguish between multiple mechanisms that can lead to certain phenotypes (e.g., cell death). Our method connected compounds with similar mechanisms of action, enabling prediction of new targets and mechanisms both for known bioactives and for compounds emerging from new screens. Furthermore, we used Bayesian modeling of promiscuous compounds to distinguish between broadly bioactive and narrowly bioactive compound communities. Several examples illustrate the utility of our method to support mechanism-of-action studies in probe development and target identification projects.


Alternate JournalJ Biomol Screen
PubMed ID24464433
Grant ListDP2-DK083048 / DK / NIDDK NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
UL1RR024924 / RR / NCRR NIH HHS / United States