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Feb 21, 2013;20 (2): 285-95.

"Function-first" lead discovery: mode of action profiling of natural product libraries using image-based screening.

Christopher J Schulze, Walter M Bray, Marcos H Woerhmann, Joshua Stuart, R Scott Lokey, Roger G Linington
Author Information
  1. Christopher J Schulze: Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
PMID: 23438757 DOI: 10.1016/j.chembiol.2012.12.007

Abstract

Cytological profiling is a high-content image-based screening technology that provides insight into the mode of action (MOA) for test compounds by directly measuring hundreds of phenotypic cellular features. We have extended this recently reported technology to the mechanistic characterization of unknown natural products libraries for the direct prediction of compound MOAs at the primary screening stage. By analyzing a training set of commercial compounds of known mechanism and comparing these profiles to those obtained from natural product library members, we have successfully annotated extracts based on MOA, dereplicated known compounds based on biological similarity to the training set, and identified and predicted the MOA of a unique family of iron siderophores. Coupled with traditional analytical techniques, cytological profiling provides an avenue for the creation of "function-first" approaches to natural products discovery.

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Grants

  1. R01 GM084530/NIGMS NIH HHS
  2. S10 RR022455/NCRR NIH HHS
  3. R01GM084530/NIGMS NIH HHS
  4. 1-S10-RR022455/NCRR NIH HHS

MeSH Term

Aquatic Organisms
Biological Products
Cell Cycle Checkpoints
Chromatography, High Pressure Liquid
Cluster Analysis
HeLa Cells
Humans
Mass Spectrometry
Microscopy, Fluorescence
Peptides, Cyclic

Chemicals

Biological Products
Peptides, Cyclic
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.
Article has an altmetric score of 8

Word Cloud

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