title: Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.
abstract: The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Alice E
authors: AE
authors: Williamson
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Paul M
authors: PM
authors: Ylioja
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Murray N
authors: MN
authors: Robertson
authors: Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Yevgeniya
authors: Y
authors: Antonova-Koch
authors: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors: Vicky
authors: V
authors: Avery
authors: Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors: Jonathan B
authors: JB
authors: Baell
authors: CSIR-Central Drug Research Institute , Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India.
authors: Harikrishna
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authors: Batchu
authors: CSIR-Central Drug Research Institute , Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India.
authors: Sanjay
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authors: Batra
authors: Medicines for Malaria Venture , PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland.
authors: Jeremy N
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authors: CSIR-Central Drug Research Institute , Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India.
authors: Soumya
authors: S
authors: Bhattacharyya
authors: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Felix
authors: F
authors: Calderon
authors: Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors: Susan A
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authors: Charman
authors: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital , MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States.
authors: Julie
authors: J
authors: Clark
authors: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Benigno
authors: B
authors: Crespo
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Matin
authors: M
authors: Dean
authors: Department of Chemistry, Lawrence University , 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911, United States.
authors: Stefan L
authors: SL
authors: Debbert
authors: Department of Life Sciences, Imperial College London , South Kensington, London SW7 2AZ, U.K.
authors: Michael
authors: M
authors: Delves
authors: Research School of Biology, The Australian National University , Canberra, ACT 2601, Australia.
authors: Adelaide S M
authors: AS
authors: Dennis
authors: Asclepia Outsourcing Solutions , Damvalleistraat 49, B-9070 Destelbergen, Belgium.
authors: Frederik
authors: F
authors: Deroose
authors: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors: Sandra
authors: S
authors: Duffy
authors: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
authors: Sabine
authors: S
authors: Fletcher
authors: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.
authors: Guri
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authors: Giaever
authors: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee, DD1 5EH, U.K.
authors: Irene
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authors: Hallyburton
authors: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Francisco-Javier
authors: FJ
authors: Gamo
authors: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.
authors: Marinella
authors: M
authors: Gebbia
authors: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital , MS 1000, Room E9050, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States.
authors: R Kiplin
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authors: Guy
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Zoe
authors: Z
authors: Hungerford
authors: Research School of Biology, The Australian National University , Canberra, ACT 2601, Australia.
authors: Kiaran
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authors: Kirk
authors: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Maria J
authors: MJ
authors: Lafuente-Monasterio
authors: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.
authors: Anna
authors: A
authors: Lee
authors: Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Stephan
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authors: Meister
authors: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.
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authors: European Molecular Biology Laboratory-European Bioinformatics Institute , Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
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authors: Overington
authors: European Molecular Biology Laboratory-European Bioinformatics Institute , Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
authors: George
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authors: Papadatos
authors: Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL) , Lausanne 1015, Switzerland.
authors: Luc
authors: L
authors: Patiny
authors: Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors: James
authors: J
authors: Pham
authors: Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors: Stuart A
authors: SA
authors: Ralph
authors: Department of Life Sciences, Imperial College London , South Kensington, London SW7 2AZ, U.K.
authors: Andrea
authors: A
authors: Ruecker
authors: Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors: Eileen
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authors: Ryan
authors: IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh , Edinburgh, EH8 9XD, U.K.
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authors: CSIR-Central Drug Research Institute , Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India.
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authors: Cambridge MedChem Consulting , 8 Mangers Lane, Duxford, Cambridge CB22 4RN, U.K.
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authors: Matthew J
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authors: School of Chemistry, The University of Edinburgh , Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
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authors: Thomson
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
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authors: European Molecular Biology Laboratory-European Bioinformatics Institute , Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
authors: Iain M
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authors: Medicines for Malaria Venture , PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland.
authors: Timothy N C
authors: TN
authors: Wells
authors: Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors: Karen
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authors: White
authors: School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors: Laura
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authors: White
authors: Medicines for Malaria Venture , PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland.
authors: Paul
authors: P
authors: Willis
authors: Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors: Elizabeth A
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authors: Winzeler
authors: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4051 Basel, Switzerland.
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