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PLoS Pathog. 2016 Jul 28;12(7):e1005763. doi: 10.1371/journal.ppat.1005763. eCollection 2016.

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

Van Voorhis WC1, Adams JH2, Adelfio R3,4, Ahyong V5, Akabas MH6, Alano P7, Alday A8, Alemán Resto Y9, Alsibaee A10, Alzualde A8, Andrews KT11,12, Avery SV13, Avery VM11, Ayong L14, Baker M15, Baker S16,17,18, Ben Mamoun C19, Bhatia S20, Bickle Q21, Bounaadja L22, Bowling T23, Bosch J24, Boucher LE24, Boyom FF25, Brea J26, Brennan M10, Burton A23, Caffrey CR27, Camarda G7, Carrasquilla M28, Carter D29, Belen Cassera M30, Chih-Chien Cheng K31, Chindaudomsate W32, Chubb A10, Colon BL33, Colón-López DD24, Corbett Y34, Crowther GJ1, Cowan N3,4, D'Alessandro S34, Le Dang N35, Delves M36, DeRisi JL5, Du AY37, Duffy S11, Abd El-Salam El-Sayed S38,39, Ferdig MT40, Fernández Robledo JA9, Fidock DA41, Florent I22, Fokou PV25, Galstian A42, Gamo FJ43, Gokool S44, Gold B45, Golub T42, Goldgof GM46, Guha R31, Guiguemde WA47, Gural N20, Guy RK47, Hansen MA14, Hanson KK48,49, Hemphill A50, Hooft van Huijsduijnen R51, Horii T52, Horrocks P53, Hughes TB35, Huston C54, Igarashi I38, Ingram-Sieber K3,4, Itoe MA49, Jadhav A31, Naranuntarat Jensen A55, Jensen LT32, Jiang RH2, Kaiser A56, Keiser J3,4, Ketas T45, Kicka S57, Kim S58, Kirk K59, Kumar VP19, Kyle DE2, Lafuente MJ43, Landfear S60, Lee N51, Lee S14, Lehane AM59, Li F60, Little D45, Liu L58, Llinás M28, Loza MI26, Lubar A61, Lucantoni L11, Lucet I62, Maes L63, Mancama D64, Mansour NR21, March S20, McGowan S65, Medina Vera I49, Meister S37, Mercer L23, Mestres J66, Mfopa AN25, Misra RN67, Moon S14, Moore JP45, Morais Rodrigues da Costa F68, Müller J50, Muriana A8, Nakazawa Hewitt S1, Nare B23, Nathan C45, Narraidoo N13, Nawaratna S11,12, Ojo KK1, Ortiz D60, Panic G3,4, Papadatos G69, Parapini S34, Patra K61, Pham N11, Prats S43, Plouffe DM70, Poulsen SA11, Pradhan A2, Quevedo C8, Quinn RJ11, Rice CA2, Abdo Rizk M38,71, Ruecker A36, St Onge R72, Salgado Ferreira R73, Samra J28, Robinett NG24,74, Schlecht U72, Schmitt M74, Silva Villela F73, Silvestrini F7, Sinden R75, Smith DA76, Soldati T57, Spitzmüller A66, Stamm SM24, Sullivan DJ77, Sullivan W78, Suresh S73, Suzuki BM27, Suzuki Y79, Swamidass SJ36, Taramelli D35, Tchokouaha LR25, Theron A64, Thomas D42, Tonissen KF11,80, Townson S44, Tripathi AK77, Trofimov V57, Udenze KO2, Ullah I53, Vallieres C13, Vigil E37, Vinetz JM61, Voong Vinh P16, Vu H11, Watanabe NA52, Weatherby K29, White PM78, Wilks AF81,82, Winzeler EA37, Wojcik E58, Wree M37, Wu W5, Yokoyama N38, Zollo PH25, Abla N51, Blasco B51, Burrows J51, Laleu B51, Leroy D51, Spangenberg T51, Wells T51, Willis PA51.

Author information

1
Departments of Medicine, Microbiology, and Global Health, Center for Emerging and Re-emerging Infectious Diseases (CERID) University of Washington, Seattle, Washington, United States of America.
2
Center for Global Health and Infectious Diseases Research, Department of Global Health, University of South Florida, Tampa, Florida, United States of America.
3
Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
4
University of Basel, Basel, Switzerland.
5
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of California, San Francisco, California, United States of America.
6
Departments of Physiology & Biophysics, Neuroscience and Medicine, Albert Einstein College of Medicine, New York, New York, United States of America.
7
Dipartimento Malattie Infettive, Parassitarie ed Immunomediate Istituto Superiore di Sanità, Roma, Italia.
8
BBD BioPhenix SL-BIOBIDE, Donostia, Gipuzkoa, Spain.
9
Bigelow Laboratory for Ocean Sciences, East Boothbay, Maine, United States of America.
10
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
11
Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
12
QIMR Berghofer Medical Research Institute Herston, Brisbane, Australia.
13
School of Life Sciences, University of Nottingham, Nottingham, Nottinghamshire, England, United Kingdom.
14
Institut Pasteur Korea, Pangyo Techno-Valley, Gyeonggi Province, Korea.
15
Clinical Pharmacology, Novartis Consumer Health, Nyon, Switzerland.
16
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
17
Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford, England, United Kingdom.
18
The London School of Hygiene and Tropical Medicine, London, England, United Kingdom.
19
Internal Medicine, Yale University, New Haven, Connecticut, United States of America.
20
Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
21
Department of Immunology & Infection, London School of Hygiene and Tropical Medicine, London, England, United Kingdom.
22
Museum of National History, Sorbonne Universities, Paris, France.
23
SCYNEXIS, Inc., Durham, North Carolina, United States of America.
24
Department of Biochemistry and Molecular Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, Untied States of America.
25
Department of Biochemistry, University of Yaoundé, Yaoundé, Cameroon.
26
CIMUS Research Centre, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
27
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
28
Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania, United States of America.
29
School of Life and Environmental Sciences, University of Sydney, Darlington New South Wales, Australia.
30
Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
31
National Center of Advancing Translational Sciences, NIH, Bethesda, Maryland, United States of America.
32
Department of Biochemistry, Mahidol University, Bangkok, Thailand.
33
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
34
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
35
Department of Pathology and Immunology, Washington University in St Louis, St. Louis, Missouri, United States of America.
36
Department of Life Sciences, Imperial College London, London, England, United Kingdom.
37
Division of Pharmacology and Drug Discovery, Department of Pediatrics, School of Medicine University of California San Diego, La Jolla, California, United States of America.
38
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.
39
Department of Biochemistry and Chemistry of nutrition, Mansoura University, Mansoura City, Egypt.
40
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame Indiana, United States of America.
41
Department of Microbiology & Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.
42
Broad Institute, Cambridge, Massachusetts, United States of America.
43
Biochemistry and Parasitology Department, Malaria DPU, Diseases of the Developing World (DDW), GlaxoSmithKline R&D, Tres Cantos, Madrid, Spain.
44
Tropical Parasitic Diseases Unit, Northwick Park Institute for Medical Research, Harrow, Middlesex, England, United Kingdom.
45
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
46
Medical Scientist Training Program, University of California, San Diego, San Diego, California, United States of America.
47
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
48
Dept. of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, San Antonio, Texas, United States of America.
49
Instituto de Medicina Molecular, Lisboa, Portugal.
50
Institute of Parasitology, University of Berne, Bern, Switzerland.
51
Medicines for Malaria Venture, Geneva, Switzerland.
52
Global Health Research Section, hhc Data Creation Center, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
53
Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire, United Kingdom.
54
Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont, United States of America.
55
Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok Thailand.
56
Medical Research Centre, Institute for Pharmacogenetics, Essen, Germany.
57
Department of Biochemistry, University of Geneva, Geneva, Switzerland.
58
Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, Louisiana, United States of America.
59
Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
60
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States of America.
61
Department of Medicine, University of California San Diego, San Diego, California, United States of America.
62
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
63
University of Antwerp, Department of Biomedical Sciences, Antwerp, Belgium.
64
Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa.
65
Department of Microbiology, Monash University, Clayton, Australia.
66
Chemotargets S.L. and Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Institute of Medical Research and University Pompeu Fabra, Barcelona, Catalonia, Spain.
67
Division of Cancer Therapeutics and Diagnosis, Drug Synthesis and Chemistry Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
68
Graduate Program in Bioinformatics, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
69
ChEMBL group, European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, United Kingdom.
70
Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
71
Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura City, Egypt.
72
Department of Biochemistry and Stanford Genome Technology Center, Stanford University, Palo Alto, Calilfornia, United States of America.
73
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
74
Laboratoire de Chimie Moléculaire, CNRS,-UMR 7509, COB-IRJBD, Mulhouse Cedex, France.
75
The Jenner Institute, University of Oxford, Oxford, England, United Kingdom.
76
Department of Chemistry, University of Capetown, Capetown, South Africa.
77
H. Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
78
Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California, United States of America.
79
Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, California, United States of America.
80
School of Natural Sciences, Griffith University, Nathan, Queensland, Australia.
81
Hudson Institute of Medical Research; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
82
SYNthesis Research, Parkville, Victoria, Australia.

Abstract

A 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.

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