Volume 92 Issue 21 | p. 40 | Concentrates
Issue Date: May 26, 2014

To Uncover Substrates For Mystery Enzymes, Fragment-Based Approaches May Be A Poor Fit

Strategy’s success for finding enzyme inhibitors doesn’t translate to substrates in new study
Department: Science & Technology
News Channels: Biological SCENE, JACS In C&EN
Keywords: fragment-based drug discovery, chemical biology, biochemistry, metabolomics
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Small changes (red) to enzyme substrates such as adenosine dramatically reduced enzyme activity, even when the changes were far from the site where an enzymatic reaction occurs.
A set of two structures: Adenosine and an adenosine fragment, the second of which does not show activity. The change is shown in red.
 
Small changes (red) to enzyme substrates such as adenosine dramatically reduced enzyme activity, even when the changes were far from the site where an enzymatic reaction occurs.

Medicinal chemists have advanced enzyme inhibitors all the way to clinical trials and FDA approval by using fragment-based approaches—that is, by identifying chemical fragments as small as a single ring and piecing them together into high-affinity binders. That success makes researchers keen to use similar strategies to predict substrates for the scores of proteins in the human genome that have unknown functions. However, a new report concludes that fragments are unlikely to be reliable for that application (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja501354q). Prior substrate discovery studies using the fragment approach had mixed results. So Brian K. Shoichet of the University of California, San Francisco, teamed with Karen N. Allen of Boston University, Frank M. Raushel of Texas A&M University, and colleagues to probe the idea further. They systematically fragmented known substrates for enzymes from three different families then measured how well enzymes acted on each fragment. To the group’s surprise, minuscule changes obliterated enzyme activity by orders of magnitude. Even though fragments have helped researchers discover a few enzyme substrates previously, the team thinks that a library of fully elaborated metabolites will be better suited to the task.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

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