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ACS Cent Sci. 2016 Oct 26;2(10):687-701. Epub 2016 Sep 14.

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.

Author information

1
School of Chemistry, The University of Sydney , Sydney, New South Wales 2006, Australia.
2
Department of Pediatrics, Pharmacology & Drug Development, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
3
Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
4
Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
5
CSIR-Central Drug Research Institute , Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India.
6
Medicines for Malaria Venture , PO Box 1826, 20 rte de Pre-Bois, 1215 Geneva 15, Switzerland.
7
Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
8
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.
9
Department of Chemistry, Lawrence University , 233 Steitz Science Hall, 711 East Boldt Way, Appleton, Wisconsin 54911, United States.
10
Department of Life Sciences, Imperial College London , South Kensington, London SW7 2AZ, U.K.
11
Research School of Biology, The Australian National University , Canberra, ACT 2601, Australia.
12
Asclepia Outsourcing Solutions , Damvalleistraat 49, B-9070 Destelbergen, Belgium.
13
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.
14
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee, DD1 5EH, U.K.
15
European Molecular Biology Laboratory-European Bioinformatics Institute , Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, U.K.
16
Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL) , Lausanne 1015, Switzerland.
17
Department of Biochemistry & Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne , Melbourne, Victoria 3010, Australia.
18
IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh , Edinburgh, EH8 9XD, U.K.
19
Cambridge MedChem Consulting , 8 Mangers Lane, Duxford, Cambridge CB22 4RN, U.K.
20
School of Chemistry, The University of Edinburgh , Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
21
Swiss Tropical and Public Health Institute , Socinstrasse 57, 4051 Basel, Switzerland.

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.

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