1 research outputs found
Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening
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<sup>13</sup> 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