Bivalent Enzyme Inhibitors Discovered Using Dynamic Covalent Chemistry

A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione‐S‐transferase (GST) enzyme family. The dynamic covalent libraries (DCLs) use aniline‐catalysed acylhydrazone exchange between bivalent hydrazides and glutathione‐conjugat...

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Bibliographic Details
Published in:Chemistry : a European journal 2012-08, Vol.18 (34), p.10562-10570
Main Authors: Clipson, Alexandra J., Bhat, Venugopal T., McNae, Iain, Caniard, Anne M., Campopiano, Dominic J., Greaney, Michael F.
Format: Article
Language:English
Subjects:
Affinity
Aniline Compounds - chemistry
Aniline Compounds - pharmacology
Animals
Binding Sites
Catalysis
Chemistry
Covalence
drug design
dynamic covalent chemistry
Dynamical systems
Dynamics
Enzymes
Glutathione Transferase - antagonists & inhibitors
Humans
hydrazones
Hydrazones - chemistry
Hydrazones - pharmacology
inhibitors
Models, Molecular
Molecular Structure
Nanostructure
Proteins
Schistosoma japonicum - enzymology
Schistosoma japonicum - immunology
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Summary:A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione‐S‐transferase (GST) enzyme family. The dynamic covalent libraries (DCLs) use aniline‐catalysed acylhydrazone exchange between bivalent hydrazides and glutathione‐conjugated aldehydes and the bis‐hydrazides act as linkers to bridge between each glutathione binding site. The resultant DCLs were found to be compatible and highly responsive to templating with different GST isozymes, with the best results coming from the M and Schistosoma japonicum (Sj) class of GSTs, targets in cancer and tropical disease, respectively. The approach yielded compounds with selective, nanomolar affinity (Ki=61 nM for mGSTM1‐1) and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein. Library powers: A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione‐S‐transferase (GST) enzyme family. The approach (see scheme) yielded compounds with selective, nanomolar affinity and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201201507