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dc.contributor.authorRudrawar, Santosh
dc.contributor.authorMakwana, Vivek
dc.contributor.authorRyan, Philip
dc.contributor.authorMalde, Alpeshkumar K
dc.contributor.authorAnoopkumar-Dukie, Shailendra
dc.date.accessioned2020-10-13T04:33:09Z
dc.date.available2020-10-13T04:33:09Z
dc.date.issued2020
dc.identifier.issn1860-7179
dc.identifier.doi10.1002/cmdc.202000582
dc.identifier.urihttp://hdl.handle.net/10072/398295
dc.description.abstractThe O -linked β- N -acetylglucosamine (O -GlcNAc) transferase (OGT) is a master regulator of installing O -GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins with varying functional classes including translational factors, transcription factors, signaling proteins, phosphate kinase are OGT substrates. Aberrant O-GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. The selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors having micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofjournalChemMedChem
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.subject.keywordsBisubstrate inhibitors
dc.subject.keywordsO-GlcNAcylation
dc.subject.keywordsOGT enzyme
dc.subject.keywordsOGT inhibitors
dc.subject.keywordsPost-translational modification
dc.titleBisubstrate ether-linked uridine-peptide conjugates as O-GlcNAc transferase inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationRudrawar, S; Makwana, V; Ryan, P; Malde, AK; Anoopkumar-Dukie, S, Bisubstrate ether-linked uridine-peptide conjugates as O-GlcNAc transferase inhibitors., ChemMedChem, 2020
dcterms.dateAccepted2020-09-25
dc.date.updated2020-10-12T00:35:29Z
dc.description.versionAccepted Manuscript (AM)
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version.
gro.rights.copyright© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: Bisubstrate ether‐linked uridine‐peptide conjugates as O‐GlcNAc transferase inhibitors, ChemMedChem, Accepted Articles, 2020, which has been published in final form at 10.1002/cmdc.202000582. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html)
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gro.griffith.authorAnoopkumar-Dukie, Shailendra
gro.griffith.authorRudrawar, Santosh
gro.griffith.authorMakwana, Vivek M.
gro.griffith.authorRyan, Philip
gro.griffith.authorMalde, Alpesh K.


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