Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

dc.contributor.authorVan Voorhis, Wesley C.en
dc.contributor.authorAdams, John H.en
dc.contributor.authorAdelfio, Robertoen
dc.contributor.authorAhyong, Vidaen
dc.contributor.authorAkabas, Myles H.en
dc.contributor.authorAlano, Pietroen
dc.contributor.authorAlday, Aintzaneen
dc.contributor.authorResto, Yesmalie Alemanen
dc.contributor.authorAlsibaee, Aishahen
dc.contributor.authorAlzualde, Ainhoaen
dc.contributor.authorAndrews, Katherine T.en
dc.contributor.authorAvery, Simon V.en
dc.contributor.authorAvery, Vicky M.en
dc.contributor.authorAyong, Lawrenceen
dc.contributor.authorBaker, Marken
dc.contributor.authorBaker, Stephenen
dc.contributor.authorBen Mamoun, Choukrien
dc.contributor.authorBhatia, Sangeetaen
dc.contributor.authorBickle, Quentinen
dc.contributor.authorBounaadja, Lotfien
dc.contributor.authorBowling, Tanaen
dc.contributor.authorBosch, Juergenen
dc.contributor.authorBoucher, Lauren E.en
dc.contributor.authorBoyom, Fabrice F.en
dc.contributor.authorBrea, Joseen
dc.contributor.authorBrennan, Marianen
dc.contributor.authorBurton, Audreyen
dc.contributor.authorCaffrey, Conor R.en
dc.contributor.authorCamarda, Graziaen
dc.contributor.authorCarrasquilla, Manuelaen
dc.contributor.authorCarter, Deeen
dc.contributor.authorCassera, Maria B.en
dc.contributor.authorCheng, Ken Chih-Chienen
dc.contributor.authorChindaudomsate, Worathaden
dc.contributor.authorChubb, Anthonyen
dc.contributor.authorColon, Beatrice L.en
dc.contributor.authorColon-Lopez, Daisy D.en
dc.contributor.authorCorbett, Yolandaen
dc.contributor.authorCrowther, Gregory J.en
dc.contributor.authorCowan, Noemien
dc.contributor.authorD'Alessandro, Sarahen
dc.contributor.authorLe Dang, Naen
dc.contributor.authorDelves, Michaelen
dc.contributor.authorDeRisi, Joseph L.en
dc.contributor.authorDu, Alan Y.en
dc.contributor.authorDuffy, Sandraen
dc.contributor.authorEl-Sayed, Shimaa Abd El-Salamen
dc.contributor.authorFerdig, Michael T.en
dc.contributor.authorRobledo, Jose A. Fernandezen
dc.contributor.authorFidock, David A.en
dc.contributor.authorFlorent, Isabelleen
dc.contributor.authorFokou, Patrick V. T.en
dc.contributor.authorGalstian, Anien
dc.contributor.authorJavier Gamo, Franciscoen
dc.contributor.authorGokool, Suzanneen
dc.contributor.authorGold, Benen
dc.contributor.authorGolub, Todden
dc.contributor.authorGoldgof, Gregory M.en
dc.contributor.authorGuha, Rajarshien
dc.contributor.authorGuiguemde, W. Armanden
dc.contributor.authorGural, Nilen
dc.contributor.authorGuy, R. Kiplinen
dc.contributor.authorHansen, Michael A. E.en
dc.contributor.authorHanson, Kirsten K.en
dc.contributor.authorHemphill, Andrewen
dc.contributor.authorvan Huijsduijnen, Rob Hooften
dc.contributor.authorHorii, Takaakien
dc.contributor.authorHorrocks, Paulen
dc.contributor.authorHughes, Tyler B.en
dc.contributor.authorHuston, Christopheren
dc.contributor.authorIgarashi, Ikuoen
dc.contributor.authorIngram-Sieber, Katrinen
dc.contributor.authorItoe, Maurice A.en
dc.contributor.authorJadhav, Ajiten
dc.contributor.authorJensen, Amornrat Naranuntaraten
dc.contributor.authorJensen, Laran T.en
dc.contributor.authorJiang, Rays H. Y.en
dc.contributor.authorKaiser, Annetteen
dc.contributor.authorKeiser, Jenniferen
dc.contributor.authorKetas, Thomasen
dc.contributor.authorKicka, Sebastienen
dc.contributor.authorKim, Sunyoungen
dc.contributor.authorKirk, Kiaranen
dc.contributor.authorKumar, Vidya P.en
dc.contributor.authorKyle, Dennis E.en
dc.contributor.authorJose Lafuente, Mariaen
dc.contributor.authorLandfear, Scotten
dc.contributor.authorLee, Nathanen
dc.contributor.authorLee, Sukjunen
dc.contributor.authorLehane, Adele M.en
dc.contributor.authorLi, Fengwuen
dc.contributor.authorLittle, Daviden
dc.contributor.authorLiu, Liqiongen
dc.contributor.authorLlinas, Manuelen
dc.contributor.authorLoza, Maria I.en
dc.contributor.authorLubar, Aristeaen
dc.contributor.authorLucantoni, Leonardoen
dc.contributor.authorLucet, Isabelleen
dc.contributor.authorMaes, Louisen
dc.contributor.authorMancama, Daluen
dc.contributor.authorMansour, Nuha R.en
dc.contributor.authorMarch, Sandraen
dc.contributor.authorMcGowan, Sheenaen
dc.contributor.authorVera, Iset Medinaen
dc.contributor.authorMeister, Stephanen
dc.contributor.authorMercer, Lukeen
dc.contributor.authorMestres, Jordien
dc.contributor.authorMfopa, Alvine N.en
dc.contributor.authorMisra, Raj N.en
dc.contributor.authorMoon, Seunghyunen
dc.contributor.authorMoore, John P.en
dc.contributor.authorRodrigues da Costa, Francielly Moraisen
dc.contributor.authorMueller, Joachimen
dc.contributor.authorMuriana, Arantzaen
dc.contributor.authorHewitt, Stephen Nakazawaen
dc.contributor.authorNare, Bakelaen
dc.contributor.authorNathan, Carlen
dc.contributor.authorNarraidoo, Nathalieen
dc.contributor.authorNawaratna, Sujeevien
dc.contributor.authorOjo, Kayode K.en
dc.contributor.authorOrtiz, Dianaen
dc.contributor.authorPanic, Gordanaen
dc.contributor.authorPapadatos, Georgeen
dc.contributor.authorParapini, Silviaen
dc.contributor.authorPatra, Kailashen
dc.contributor.authorNgoc Phamen
dc.contributor.authorPrats, Sarahen
dc.contributor.authorPlouffe, David M.en
dc.contributor.authorPoulsen, Sally-Annen
dc.contributor.authorPradhan, Anupamen
dc.contributor.authorQuevedo, Celiaen
dc.contributor.authorQuinn, Ronald J.en
dc.contributor.authorRice, Christopher A.en
dc.contributor.authorRizk, Mohamed Abdoen
dc.contributor.authorRuecker, Andreaen
dc.contributor.authorSt Onge, Roberten
dc.contributor.authorFerreira, Rafaela Salgadoen
dc.contributor.authorSamra, Jasmeeten
dc.contributor.authorRobinett, Natalie G.en
dc.contributor.authorSchlecht, Ulrichen
dc.contributor.authorSchmitt, Marjorieen
dc.contributor.authorVillela, Filipe Silvaen
dc.contributor.authorSilvestrini, Francescoen
dc.contributor.authorSinden, Roberten
dc.contributor.authorSmith, Dennis A.en
dc.contributor.authorSoldati, Thierryen
dc.contributor.authorSpitzmueller, Andreasen
dc.contributor.authorStamm, Serge Maximilianen
dc.contributor.authorSullivan, David J.en
dc.contributor.authorSullivan, William G.en
dc.contributor.authorSuresh, Sundarien
dc.contributor.authorSuzuki, Brian M.en
dc.contributor.authorSuzuki, Yoen
dc.contributor.authorSwamidass, S. Joshuaen
dc.contributor.authorTaramelli, Donatellaen
dc.contributor.authorTchokouaha, Lauve R. Y.en
dc.contributor.authorTheron, Anjoen
dc.contributor.authorThomas, Daviden
dc.contributor.authorTonissen, Kathryn F.en
dc.contributor.authorTownson, Simonen
dc.contributor.authorTripathi, Abhai K.en
dc.contributor.authorTrofimov, Valentinen
dc.contributor.authorUdenze, Kenneth O.en
dc.contributor.authorUllah, Imranen
dc.contributor.authorVallieres, Cindyen
dc.contributor.authorVigil, Edgaren
dc.contributor.authorVinetz, Joseph M.en
dc.contributor.authorPhat Voong Vinhen
dc.contributor.authorHoan Vuen
dc.contributor.authorWatanabe, Nao-akien
dc.contributor.authorWeatherby, Kateen
dc.contributor.authorWhite, Pamela M.en
dc.contributor.authorWilks, Andrew F.en
dc.contributor.authorWinzeler, Elizabeth A.en
dc.contributor.authorWojcik, Edwarden
dc.contributor.authorWree, Melanieen
dc.contributor.authorWu, Wesleyen
dc.contributor.authorYokoyama, Naoakien
dc.contributor.authorZollo, Paul H. A.en
dc.contributor.authorAbla, Nadaen
dc.contributor.authorBlasco, Benjaminen
dc.contributor.authorBurrows, Jeremyen
dc.contributor.authorLaleu, Benoiten
dc.contributor.authorLeroy, Didieren
dc.contributor.authorSpangenberg, Thomasen
dc.contributor.authorWells, Timothyen
dc.contributor.authorWillis, Paul A.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2018-12-04T18:42:14Zen
dc.date.available2018-12-04T18:42:14Zen
dc.date.issued2016-07-28en
dc.description.abstractA major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.en
dc.description.sponsorshipThanks to the UK DFID and the Bill and Melinda Gates Foundation Grand Challenges Explorations for providing funding for testing of the Malaria Box and funding the support of individual groups including: Medicines for Malaria Venture MMV Challenge Grant, Grant Numbers MMV 12/0048 and MMV 12/0076 (to JHA), the Australian Research Council (FT10100185 to SAP; FT0991213 to KTA and LP120200557 awarded to VMA), Bill & Melinda Gates Foundation Grant OPP1040394 to PA, OPP1040399 to DAF and VMA and OPP1086189 to KKH, OPP1069393 and OPP1119049 to ML, OPP1024029 to CN, the Bloomberg Family Foundation (JBr), JHMRI for a predoctoral fellowship, the US NIH for the CBI training grant T32GM080189 (to LEB), R01GM104486 (to PAW & WS), R01AI117017 (to JHA) the National Science Foundation Graduate Research Fellowship Program Grant No. DGE-1232825 (DDCL), the South African Medical Research Council Strategic Health Innovation Partnerships (grant V6YBT51 to DM) and the Council for Scientific and Industrial Research (grant V1YTB95, to DM), and the French ANR program Mammamia (ANR-12-BS07-0020-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.format.extent23 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1005763en
dc.identifier.eissn1553-7374en
dc.identifier.issn1553-7366en
dc.identifier.issue7en
dc.identifier.othere1005763en
dc.identifier.pmid27467575en
dc.identifier.urihttp://hdl.handle.net/10919/86219en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectstage plasmodium-falciparumen
dc.subjectin-vitroen
dc.subjectinfected erythrocytesen
dc.subjecttheileria parasitesen
dc.subjectidentificationen
dc.subjectinhibitorsen
dc.subjecttransmissionen
dc.subjecttargeten
dc.subjectbabesiaen
dc.subjectblooden
dc.titleOpen Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyonden
dc.title.serialPLOS Pathogensen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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