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dc.contributor.authorChua, Ming Jang
dc.contributor.authorRobaa, Dina
dc.contributor.authorSkinner-Adams, Tina S
dc.contributor.authorSippl, Wolfgang
dc.contributor.authorAndrews, Katherine T
dc.date.accessioned2019-05-29T13:07:11Z
dc.date.available2019-05-29T13:07:11Z
dc.date.issued2018
dc.identifier.issn2211-3207
dc.identifier.doi10.1016/j.ijpddr.2018.03.001
dc.identifier.urihttp://hdl.handle.net/10072/380735
dc.description.abstractBromodomain-containing proteins (BDPs) are involved in the regulation of eukaryotic gene expression. Compounds that bind and/or inhibit BDPs are of interest as tools to better understand epigenetic regulation, and as possible drug leads for different diseases, including malaria. In this study, we assessed the activity of 42 compounds demonstrated or predicted (using virtual screening of a pharmacophore model) to bind/inhibit eukaryotic BDPs for activity against Plasmodium falciparum malaria parasites. In silico docking studies indicated that all compounds are predicted to participate in a typical hydrogen bond interaction with the conserved asparagine (Asn1436) of the P. falciparum histone acetyltransferase (PfGCN5) bromodomain and a conserved water molecule. Only one compound (the dimethylisoxazole SGC-CBP30; a selective inhibitor of CREBBP (CBP) and EP300 bromodomains) is also predicted to have a salt-bridge between the morpholine nitrogen and Glu1389. When tested for in vitro activity against asynchronous asexual stage P. falciparum Dd2 parasites, all compounds displayed 50% growth inhibitory concentrations (IC50) >10 μM. Further testing of the three most potent compounds using synchronous parasites for 72 h showed that SGC-CBP30 was the most active (IC50 3.2 μM). In vitro cytotoxicity assays showed that SGC-CBP30 has ∼7-fold better selectivity for the parasites versus a human cell line (HEK 293). Together these data provide a possible starting point for future investigation of these, or related compounds, as tools to understand epigenetic regulation or as potential new drug leads.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.publisher.placeUnited Kingdom
dc.relation.ispartofpagefrom189
dc.relation.ispartofpageto193
dc.relation.ispartofissue2
dc.relation.ispartofjournalInternational Journal for Parasitology: Drugs and Drug Resistance
dc.relation.ispartofvolume8
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchMedical microbiology not elsewhere classified
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode320799
dc.titleActivity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.description.versionVersion of Record (VoR)
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.rights.copyright© 2018 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorAndrews, Katherine T.
gro.griffith.authorSkinner-Adams, Tina
gro.griffith.authorChua, MJ J.


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