title: Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening.
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|Pharmacology and Toxicology Graduate Group, University of California, Davis , Davis, California 95616, United States.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|Genetic Graduate Group, University of California , Davis, California 95616, United States.
authors.forename: Don-Hong
authors.initials: DH
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Dixon
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Ahadi
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|Center for Biophotonics Science and Technology, University of California, Davis , Sacramento, California 95817, United States.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Enter
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|Pharmacology and Toxicology Graduate Group, University of California, Davis , Davis, California 95616, United States.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Pharmacology and Toxicology Graduate Group, University of California, Davis , Davis, California 95616, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Kato
authors.affiliation: Pharmacology and Toxicology Graduate Group, University of California, Davis , Davis, California 95616, United States.
authors.forename: Leonardo J
authors.initials: LJ
authors.lastname: Leon
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|Center for Biophotonics Science and Technology, University of California, Davis , Sacramento, California 95817, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Ramirez
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Carolina F
authors.initials: CF
authors.lastname: Reis
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Brianna
authors.initials: B
authors.lastname: Ribeiro
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Brittany
authors.initials: B
authors.lastname: Weems
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.|National Health Research Institutes , Miaoli County 35053, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine , 2700 Stockton Boulevard, Suite 2102, Sacramento, California 95817, United States.
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008715:Methionine / Q000378:metabolism; D019151:Peptide Library; D040901:Proteomics / Q000379:methods*; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018076:DNA, Complementary; D008024:Ligands; D019151:Peptide Library; D054852:Small Molecule Libraries; D008715:Methionine
keywords: library-against-library screening; molecular interactions; one-bead-one-compound combinatorial library; phage display cDNA expression proteome library; small molecule compound beads