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

doi:10.1021/acscombsci.5b00194

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 journal › Article › peer-review

9 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 language	English
Pages (from-to)	320-329
Number of pages	10
Journal	ACS Combinatorial Science
Volume	18
Issue number	6
DOIs	https://doi.org/10.1021/acscombsci.5b00194
Publication status	Published - Jun 13 2016
Externally published	Yes

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

General Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acscombsci.5b00194

Cite this

Wu, C. Y., Wang, D. H., Wang, X., Dixon, S. M., Meng, L., Ahadi, S., Enter, D. H., Chen, C. Y., Kato, J., Leon, L. J., Ramirez, L. M., Maeda, Y., Reis, C. F., Ribeiro, B., Weems, B., Kung, H. J., & Lam, K. S. (2016). Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening. ACS Combinatorial Science, 18(6), 320-329. https://doi.org/10.1021/acscombsci.5b00194

Wu, CY, Wang, DH, Wang, X, Dixon, SM, Meng, L, Ahadi, S, Enter, DH, Chen, CY, Kato, J, Leon, LJ, Ramirez, LM, Maeda, Y, Reis, CF, Ribeiro, B, Weems, B, Kung, HJ & Lam, KS 2016, 'Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening', ACS Combinatorial Science, vol. 18, no. 6, pp. 320-329. https://doi.org/10.1021/acscombsci.5b00194

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AU - Leon, Leonardo J.

AU - Ramirez, Laura M.

AU - Maeda, Yoshiko

AU - Reis, Carolina F.

AU - Ribeiro, Brianna

AU - Weems, Brittany

AU - Kung, Hsing Jien

AU - Lam, Kit S.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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