Title

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

Authors

Wesley C. Van Voorhis, 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.
John H. Adams, Center for Global Health and Infectious Diseases Research, Department of Global Health, University of South Florida, Tampa, Florida, United States of America.
Roberto Adelfio, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
Vida Ahyong, Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of California, San Francisco, California, United States of America.
Myles H. Akabas, Departments of Physiology & Biophysics, Neuroscience and Medicine, Albert Einstein College of Medicine, New York, New York, United States of America.
Pietro Alano, Dipartimento Malattie Infettive, Parassitarie ed Immunomediate Istituto Superiore di Sanità, Roma, Italia.
Aintzane Alday, BBD BioPhenix SL-BIOBIDE, Donostia, Gipuzkoa, Spain.
Yesmalie Alemán Resto, Bigelow Laboratory for Ocean Sciences, East Boothbay, Maine, United States of America.
Aishah Alsibaee, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Ainhoa Alzualde, BBD BioPhenix SL-BIOBIDE, Donostia, Gipuzkoa, Spain.
Katherine T. Andrews, Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
Simon V. Avery, School of Life Sciences, University of Nottingham, Nottingham, Nottinghamshire, England, United Kingdom.
Vicky M. Avery, Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
Lawrence Ayong, Institut Pasteur Korea, Pangyo Techno-Valley, Gyeonggi Province, Korea.
Mark Baker, Clinical Pharmacology, Novartis Consumer Health, Nyon, Switzerland.
Stephen Baker, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Choukri Ben Mamoun, Internal Medicine, Yale University, New Haven, Connecticut, United States of America.
Sangeeta Bhatia, Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Quentin Bickle, Department of Immunology & Infection, London School of Hygiene and Tropical Medicine, London, England, United Kingdom.
Lotfi Bounaadja, Museum of National History, Sorbonne Universities, Paris, France.
Tana Bowling, SCYNEXIS, Inc., Durham, North Carolina, United States of America.
Jürgen Bosch, 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.
Lauren E. Boucher, 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.
Fabrice F. Boyom, Department of Biochemistry, University of Yaoundé, Yaoundé, Cameroon.
Jose Brea, CIMUS Research Centre, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
Marian Brennan, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Audrey Burton, SCYNEXIS, Inc., Durham, North Carolina, United States of America.
Conor R. Caffrey, Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Grazia Camarda, Dipartimento Malattie Infettive, Parassitarie ed Immunomediate Istituto Superiore di Sanità, Roma, Italia.
Manuela Carrasquilla, Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania, United States of America.
Dee Carter, School of Life and Environmental Sciences, University of Sydney, Darlington New South Wales, Australia.
Maria Belen Cassera, Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
Ken Chih-Chien Cheng, National Center of Advancing Translational Sciences, NIH, Bethesda, Maryland, United States of America.

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.

Publication Title

PLoS pathogens

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