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An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.

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cam.issuedOnline2021-11-08
dc.contributor.authorTse, Edwin G
dc.contributor.authorAithani, Laksh
dc.contributor.authorAnderson, Mark
dc.contributor.authorCardoso-Silva, Jonathan
dc.contributor.authorCincilla, Giovanni
dc.contributor.authorConduit, Gareth J
dc.contributor.authorGalushka, Mykola
dc.contributor.authorGuan, Davy
dc.contributor.authorHallyburton, Irene
dc.contributor.authorIrwin, Benedict WJ
dc.contributor.authorKirk, Kiaran
dc.contributor.authorLehane, Adele M
dc.contributor.authorLindblom, Julia CR
dc.contributor.authorLui, Raymond
dc.contributor.authorMatthews, Slade
dc.contributor.authorMcCulloch, James
dc.contributor.authorMotion, Alice
dc.contributor.authorNg, Ho Leung
dc.contributor.authorÖeren, Mario
dc.contributor.authorRobertson, Murray N
dc.contributor.authorSpadavecchio, Vito
dc.contributor.authorTatsis, Vasileios A
dc.contributor.authorvan Hoorn, Willem P
dc.contributor.authorWade, Alexander D
dc.contributor.authorWhitehead, Thomas M
dc.contributor.authorWillis, Paul
dc.contributor.authorTodd, Matthew H
dc.contributor.orcidTse, Edwin G [0000-0002-9133-9274]
dc.contributor.orcidCincilla, Giovanni [0000-0002-5242-0707]
dc.contributor.orcidGuan, Davy [0000-0001-6290-3166]
dc.contributor.orcidLehane, Adele M [0000-0002-0050-9101]
dc.contributor.orcidMatthews, Slade [0000-0002-1652-543X]
dc.contributor.orcidMotion, Alice [0000-0002-5859-7888]
dc.contributor.orcidNg, Ho Leung [0000-0002-6415-1938]
dc.contributor.orcidRobertson, Murray N [0000-0001-9543-7667]
dc.contributor.orcidWade, Alexander D [0000-0003-1500-3733]
dc.contributor.orcidTodd, Matthew H [0000-0001-7096-4751]
dc.date.accessioned2021-11-17T00:30:38Z
dc.date.available2021-11-17T00:30:38Z
dc.date.issued2021-11-25
dc.description.abstractThe Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.
dc.identifier.doi10.17863/CAM.78136
dc.identifier.eissn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330691
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/acs.jmedchem.1c00313
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAntimalarials
dc.subjectCalcium-Transporting ATPases
dc.subjectDrug Discovery
dc.subjectEnzyme Inhibitors
dc.subjectHumans
dc.subjectModels, Biological
dc.subjectPlasmodium falciparum
dc.subjectStructure-Activity Relationship
dc.titleAn Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.
dc.typeArticle
prism.publicationDate2021
prism.publicationNameJ Med Chem
pubs.funder-project-idThe Royal Society (uf130122)
pubs.funder-project-idRoyal Society (RGF/EA/180034)
pubs.funder-project-idRoyal Society (URF\R\201002)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/L015552/1)
rioxxterms.licenseref.startdate2021-11-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acs.jmedchem.1c00313

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