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

Chun Yi Wu, Don Hong Wang, Xiaobing Wang, Seth M. Dixon, Liping Meng, Sara Ahadi, Daniel H. Enter, Chao Yu Chen, Jason Kato, Leonardo J. Leon, Laura M. Ramirez, Yoshiko Maeda, Carolina F. Reis, Brianna Ribeiro, Brittany Weems, Hsing Jien Kung, Kit S. Lam

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 1013 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.

Original languageEnglish
Pages (from-to)320-329
Number of pages10
JournalACS Combinatorial Science
Volume18
Issue number6
DOIs
Publication statusPublished - Jun 13 2016
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Chemistry(all)

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