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Molecules 2016, 21(7), 910; doi:10.3390/molecules21070910

Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery

School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand
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Academic Editors: Raymond S. Norton and Martin J. Scanlon
Received: 25 April 2016 / Revised: 4 July 2016 / Accepted: 8 July 2016 / Published: 16 July 2016
(This article belongs to the Special Issue Developments in Fragment-Based Lead Discovery)
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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. View Full-Text
Keywords: dynamic combinatorial chemistry; enzyme inhibition; ligand screening; drug discovery; ligand binding; reversible reaction; biophysical techniques dynamic combinatorial chemistry; enzyme inhibition; ligand screening; drug discovery; ligand binding; reversible reaction; biophysical techniques
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Huang, R.; Leung, I.K.H. Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery. Molecules 2016, 21, 910.

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