Hottin, Audrey, Wright, Daniel W., Moreno-Clavijo, Elena et al. (3 more authors) (2016) Exploring the divalent effect in fucosidase inhibition with stereoisomeric pyrrolidine dimers. Organic and Biomolecular Chemistry. pp. 4718-4727. ISSN 1477-0539
Abstract
Multi-valent inhibitors offer promise for the enhancement of therapeutic compounds across a range of chemical and biological processes. Here, a significant increase in enzyme-inhibition potencies was observed with a dimeric iminosugar-templated fucosidase inhibitor (IC50 = 0.108 μM) when compared to its monovalent equivalent (IC50 = 2.0 μM). Such a gain in binding is often attributed to a "multivalent effect" rising from alternative recapture of the scaffolded binding epitopes. The use of control molecules such as the meso analogue (IC50 = 0.365 μM) or the enantiomer (IC50 = 569 μM), as well as structural analysis of the fucosidase-inhibitor complex, allowed a detailed analysis of the possible mechanism of action, at the molecular level. Here, the enhanced binding affinity of the dimer over the monomer can be attributed to additional interactions in non-catalytic sites as also revealed in the 3-D structure of a bacterial fucosidase inhibitor complex.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Royal Society of Chemistry 2016. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 13 Sep 2016 13:02 |
Last Modified: | 26 Mar 2025 00:07 |
Published Version: | https://doi.org/10.1039/c6ob00647g |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1039/c6ob00647g |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:104259 |