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ACS Comb Sci. 2016 Jun 13;18(6):320-9. doi: 10.1021/acscombsci.5b00194. Epub 2016 May 3.

Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening.

Author information

1
Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
2
Pharmacology and Toxicology Graduate Group, University of California, Davis , Davis, California 95616, United States.
3
Genetic Graduate Group, University of California , Davis, California 95616, United States.
4
Center for Biophotonics Science and Technology, University of California, Davis , Sacramento, California 95817, United States.
5
National Health Research Institutes , Miaoli County 35053, Taiwan.

Abstract

Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.

KEYWORDS:

library-against-library screening; molecular interactions; one-bead-one-compound combinatorial library; phage display cDNA expression proteome library; small molecule compound beads

PMID:
27053324
PMCID:
PMC4908505
DOI:
10.1021/acscombsci.5b00194
[Indexed for MEDLINE]
Free PMC Article

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