Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
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Author(s)
Adams, John H
Adelfio, Roberto
Ahyong, Vida
Akabas, Myles H
Alano, Pietro
Alday, Aintzane
Resto, Yesmalie Aleman
Alsibaee, Aishah
Alzualde, Ainhoa
Andrews, Katherine T
Avery, Simon V
Avery, Vicky M
Ayong, Lawrence
Baker, Mark
Baker, Stephen
Ben Mamoun, Choukri
Bhatia, Sangeeta
Bickle, Quentin
Bounaadja, Lotfi
Bowling, Tana
Bosch, Juergen
Boucher, Lauren E
Boyom, Fabrice F
Brea, Jose
Brennan, Marian
Burton, Audrey
Caffrey, Conor R
Camarda, Grazia
Carrasquilla, Manuela
Carter, Dee
Cassera, Maria Belen
Cheng, Ken Chih-Chien
Chindaudomsate, Worathad
Chubb, Anthony
Colon, Beatrice L
Colon-Lopez, Daisy D
Corbett, Yolanda
Crowther, Gregory J
Cowan, Noemi
D'Alessandro, Sarah
Le Dang, Na
Delves, Michael
DeRisi, Joseph L
Du, Alan Y
Duffy, Sandra
El-Sayed, Shimaa Abd El-Salam
Ferdig, Michael T
Robledo, Jose A Fernandez
Fidock, David A
Florent, Isabelle
Fokou, Patrick VT
Galstian, Ani
Javier Gamo, Francisco
Gokool, Suzanne
Gold, Ben
Golub, Todd
Goldgof, Gregory M
Guha, Rajarshi
Guiguemde, W Armand
Gural, Nil
Guy, R Kiplin
Hansen, Michael AE
Hanson, Kirsten K
Hemphill, Andrew
van Huijsduijnen, Rob Hooft
Horii, Takaaki
Horrocks, Paul
Hughes, Tyler B
Huston, Christopher
Igarashi, Ikuo
Ingram-Sieber, Katrin
Itoe, Maurice A
Jadhav, Ajit
Jensen, Amornrat Naranuntarat
Jensen, Laran T
Jiang, Rays HY
Kaiser, Annette
Keiser, Jennifer
Ketas, Thomas
Kicka, Sebastien
Kim, Sunyoung
Kirk, Kiaran
Kumar, Vidya P
Kyle, Dennis E
Jose Lafuente, Maria
Landfear, Scott
Lee, Nathan
Lee, Sukjun
Lehane, Adele M
Li, Fengwu
Little, David
Liu, Liqiong
Llinas, Manuel
Loza, Maria I
Lubar, Aristea
Lucantoni, Leonardo
Lucet, Isabelle
Maes, Louis
Mancama, Dalu
Mansour, Nuha R
March, Sandra
McGowan, Sheena
Vera, Iset Medina
Meister, Stephan
Mercer, Luke
Mestres, Jordi
Mfopa, Alvine N
Misra, Raj N
Moon, Seunghyun
Moore, John P
Rodrigues da Costa, Francielly Morais
Mueller, Joachim
Muriana, Arantza
Hewitt, Stephen Nakazawa
Nare, Bakela
Nathan, Carl
Narraidoo, Nathalie
Nawaratna, Sujeevi
Ojo, Kayode K
Ortiz, Diana
Panic, Gordana
Papadatos, George
Parapini, Silvia
Patra, Kailash
Ngoc, Pham
Prats, Sarah
Plouffe, David M
Poulsen, Sally-Ann
Pradhan, Anupam
Quevedo, Celia
Quinn, Ronald J
Rice, Christopher A
Rizk, Mohamed Abdo
Ruecker, Andrea
St Onge, Robert
Ferreira, Rafaela Salgado
Samra, Jasmeet
Robinett, Natalie G
Schlecht, Ulrich
Schmitt, Marjorie
Villela, Filipe Silva
Silvestrini, Francesco
Sinden, Robert
Smith, Dennis A
Soldati, Thierry
Spitzmueller, Andreas
Stamm, Serge Maximilian
Sullivan, David J
Sullivan, William
Suresh, Sundari
Suzuki, Brian M
Suzuki, Yo
Swamidass, S Joshua
Taramelli, Donatella
Tchokouaha, Lauve RY
Theron, Anjo
Thomas, David
Tonissen, Kathryn F
Townson, Simon
Tripathi, Abhai K
Trofimov, Valentin
Udenze, Kenneth O
Ullah, Imran
Vallieres, Cindy
Vigil, Edgar
Vinetz, Joseph M
Phat, Voong Vinh
Hoan, Vu
Watanabe, Nao-aki
Weatherby, Kate
White, Pamela M
Wilks, Andrew F
Winzeler, Elizabeth A
Wojcik, Edward
Wree, Melanie
Wu, Wesley
Yokoyama, Naoaki
Zollo, Paul HA
Abla, Nada
Blasco, Benjamin
Burrows, Jeremy
Laleu, Benoit
Leroy, Didier
Spangenberg, Thomas
Wells, Timothy
Willis, Paul A
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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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PLoS Pathogens
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12
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7
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This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Microbiology
Immunology
Medical microbiology
Medical microbiology not elsewhere classified