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

详细信息    查看全文

• 作者：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
• 刊名：ACS Combinatorial Science
• 出版年：2016
• 出版时间：June 13, 2016
• 年：2016
• 卷：18
• 期：6
• 页码：320-329
• 全文大小：471K
• 年卷期：0
• ISSN：2156-8944

文摘

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.