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dc.contributor.authorAvery, Vicky M
dc.contributor.authorBashyam, Sridevi
dc.contributor.authorBurrows, Jeremy N
dc.contributor.authorDuffy, Sandra
dc.contributor.authorPapadatos, George
dc.contributor.authorPuthukkuti, Shyni
dc.contributor.authorSambandan, Yuvaraj
dc.contributor.authorSingh, Shivendra
dc.contributor.authorSpangenberg, Thomas
dc.contributor.authorWaterson, David
dc.contributor.authorWillis, Paul
dc.date.accessioned2017-09-28T12:30:24Z
dc.date.available2017-09-28T12:30:24Z
dc.date.issued2014
dc.identifier.issn1475-2875
dc.identifier.doi10.1186/1475-2875-13-190
dc.identifier.urihttp://hdl.handle.net/10072/103602
dc.description.abstractBackground: In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. Methods: The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. Results: This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50?<?1 卩 and selectivity (SI?>?10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. Conclusion: A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherBioMed Central
dc.publisher.placeUnited Kingdom
dc.relation.ispartofpagefrom190-1
dc.relation.ispartofpageto190-12
dc.relation.ispartofjournalMalaria Journal
dc.relation.ispartofvolume13
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchMedical microbiology not elsewhere classified
dc.subject.fieldofresearchPublic health
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode320799
dc.subject.fieldofresearchcode4206
dc.titleScreening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by/4.0
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2014 Avery et al.; licensee BioMed Central Ltd. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
gro.hasfulltextFull Text
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.


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