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Title: Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
Authors: Wesley C. Van Voorhis
John H. Adams
Roberto Adelfio
Vida Ahyong
Myles H. Akabas
Pietro Alano
Aintzane Alday
Yesmalie Alemán Resto
Aishah Alsibaee
Ainhoa Alzualde
Katherine T. Andrews
Simon V. Avery
Vicky M. Avery
Lawrence Ayong
Mark Baker
Stephen Baker
Choukri Ben Mamoun
Sangeeta Bhatia
Quentin Bickle
Lotfi Bounaadja
Tana Bowling
Jürgen Bosch
Lauren E. Boucher
Fabrice F. Boyom
Jose Brea
Marian Brennan
Audrey Burton
Conor R. Caffrey
Grazia Camarda
Manuela Carrasquilla
Dee Carter
Maria Belen Cassera
Ken Chih-Chien Cheng
Worathad Chindaudomsate
Anthony Chubb
Beatrice L. Colon
Daisy D. Colón-López
Yolanda Corbett
Gregory J. Crowther
Noemi Cowan
Sarah D’Alessandro
Na Le Dang
Michael Delves
Joseph L. DeRisi
Alan Y. Du
Sandra Duffy
Shimaa Abd El-Salam El-Sayed
Michael T. Ferdig
José A. Fernández Robledo
David A. Fidock
Isabelle Florent
Patrick V.T. Fokou
Ani Galstian
Francisco Javier Gamo
Suzanne Gokool
Ben Gold
Todd Golub
Gregory M. Goldgof
Rajarshi Guha
W. Armand Guiguemde
Nil Gural
R. Kiplin Guy
Michael A.E. Hansen
Kirsten K. Hanson
Andrew Hemphill
Rob Hooft van Huijsduijnen
Takaaki Horii
Paul Horrocks
Tyler B. Hughes
Christopher Huston
Ikuo Igarashi
Katrin Ingram-Sieber
Maurice A. Itoe
Ajit Jadhav
Amornrat Naranuntarat Jensen
Laran T. Jensen
Rays H.Y. Jiang
Annette Kaiser
Jennifer Keiser
Thomas Ketas
Sebastien Kicka
Sunyoung Kim
Kiaran Kirk
Vidya P. Kumar
Dennis E. Kyle
Maria Jose Lafuente
Scott Landfear
Nathan Lee
Sukjun Lee
Adele M. Lehane
University of Washington, Seattle
University of South Florida, Tampa
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
University of California, San Francisco
Albert Einstein College of Medicine of Yeshiva University
Istituto Superiore Di Sanita
Bigelow Laboratory for Ocean Sciences
Royal College of Surgeons in Ireland
Griffith University
QIMR Berghofer Medical Research Institute
University of Nottingham
Institut Pasteur Korea
Clinical Pharmacology and Nephrology
Nuffield Department of Clinical Medicine
London School of Hygiene & Tropical Medicine
Yale University
Massachusetts Institute of Technology
Museum National d'Histoire Naturelle
Scynexis, Inc.
Johns Hopkins Bloomberg School of Public Health
Universite de Yaounde I
Universidad de Santiago de Compostela
Pennsylvania State University
The University of Sydney
Virginia Polytechnic Institute and State University
National Center for Advancing Translational Sciences
Mahidol University
University of South Florida, Morsani College of Medicine
Università degli Studi di Milano
Washington University in St. Louis
Imperial College London
University of California, San Diego
Obihiro University of Agriculture and Veterinary Medicine
Mansoura University
University of Notre Dame
Columbia University Medical Center
Broad Institute
GlaxoSmithKline plc, Spain
Northwick Park Hospital
Weill Cornell Medical College
St. Jude Children's Research Hospital
University of Texas at San Antonio
University of Lisbon Faculty of Medicine, Institute of Molecular Medicine
University of Bern
Medicines for Malaria Venture
Eisai Co., Ltd.
Keele University
University of Vermont College of Medicine
Institute of Pharmacogenetics
Université de Genève
LSU Health Sciences Center - New Orleans
Research School of Biologyn National University
Oregon Health and Science University
Monash University
Universiteit Antwerpen
The Council for Scientific and Industrial Research
Wellcome Trust Sanger Institute
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Jul-2016
Citation: PLoS Pathogens. Vol.12, No.7 (2016)
Abstract: © 2016 Public Library of Science. All rights reserved. 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.
ISSN: 15537374
Appears in Collections:Scopus 2016-2017

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