1. Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening
- Author
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Wu, Chun-Yi, Wang, Don-Hong, Wang, Xiaobing, Dixon, Seth M, Meng, Liping, Ahadi, Sara, Enter, Daniel H, Chen, Chao-Yu, Kato, Jason, Leon, Leonardo J, Ramirez, Laura M, Maeda, Yoshiko, Reis, Carolina F, Ribeiro, Brianna, Weems, Brittany, Kung, Hsing-Jien, and Lam, Kit S
- Subjects
Biochemistry and Cell Biology ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Sciences ,Cancer ,Biotechnology ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Antineoplastic Agents ,Benzimidazoles ,Cell Cycle ,Cell Line ,Combinatorial Chemistry Techniques ,DNA ,Complementary ,Drug Discovery ,Drug Screening Assays ,Antitumor ,High-Throughput Screening Assays ,Humans ,Jurkat Cells ,Ligands ,Methionine ,Peptide Library ,Proteomics ,Small Molecule Libraries ,library-against-library screening ,one-bead-one-compound combinatorial library ,phage display cDNA expression proteome library ,molecular interactions ,small molecule compound beads ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry ,Organic chemistry - 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.
- Published
- 2016