title: Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery.
abstract: Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique. Such information is useful as a starting point to guide further organic synthesis of novel protein ligands and enzyme inhibitors. This review uses literature examples to discuss the practicalities of applying this method to inhibitor discovery, in particular, the set-up of the combinatorial library, the reversible reactions that may be employed, and the choice of detection methods to screen protein ligands from a mixture of reversibly forming molecules.
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand. rhua571@aucklanduni.ac.nz.
authors.forename: Renjie
authors.initials: R
authors.lastname: Huang
authors.affiliation: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand. i.leung@auckland.ac.nz.
authors.forename: Ivanhoe K H
authors.initials: IK
authors.lastname: Leung
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries
keywords: biophysical techniques; drug discovery; dynamic combinatorial chemistry; enzyme inhibition; ligand binding; ligand screening; reversible reaction