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dc.contributor.author
Grisoni, Francesca
dc.contributor.author
Merk, Daniel
dc.contributor.author
Byrne, Ryan
dc.contributor.author
Schneider, Gisbert
dc.date.accessioned
2018-11-21T16:56:08Z
dc.date.available
2018-11-20T05:07:11Z
dc.date.available
2018-11-21T16:56:08Z
dc.date.issued
2018-11-07
dc.identifier.other
10.1038/s41598-018-34677-0
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/304706
dc.identifier.doi
10.3929/ethz-b-000304706
dc.description.abstract
The discovery of novel ligand chemotypes allows to explore uncharted regions in chemical space, thereby potentially improving synthetic accessibility, potency, and the drug-likeness of molecules. Here, we demonstrate the scaffold-hopping ability of the new Weighted Holistic Atom Localization and Entity Shape (WHALES) molecular descriptors compared to seven state-of-the-art molecular representations on 30,000 compounds and 182 biological targets. In a prospective application, we apply WHALES to the discovery of novel retinoid X receptor (RXR) modulators. WHALES descriptors identified four agonists with innovative molecular scaffolds, populating uncharted regions of the chemical space. One of the agonists, possessing a rare non-acidic chemotype, revealed high selectivity on 12 nuclear receptors and comparable efficacy as bexarotene on induction of ATP-binding cassette transporter A1, angiopoietin like protein 4 and apolipoprotein E. The outcome of this research supports WHALES as an innovative tool to explore novel regions of the chemical space and to detect novel bioactive chemotypes by straightforward similarity searching.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature Publishing Group
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Scaffold-Hopping from Synthetic Drugs by Holistic Molecular Representation
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Scientific Reports
ethz.journal.volume
8
en_US
ethz.pages.start
16469
en_US
ethz.size
12 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2018-11-20T05:07:24Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-11-21T16:56:13Z
ethz.rosetta.lastUpdated
2019-01-03T09:38:35Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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