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

Nathan Lee
Nathan Lee
Icahn School of Medicine at Mount Sinai
New York, New York | United States
Kenneth O Udenze
Kenneth O Udenze
University of South Florida
United States
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 Sukjun Lee Adele M Lehane Fengwu Li David Little Liqiong Liu Manuel Llinás Maria I Loza Aristea Lubar Leonardo Lucantoni Isabelle Lucet Louis Maes Dalu Mancama Nuha R Mansour Sandra March Sheena McGowan Iset Medina Vera Stephan Meister Luke Mercer Jordi Mestres Alvine N Mfopa Raj N Misra Seunghyun Moon John P Moore Francielly Morais Rodrigues da Costa Joachim Müller Arantza Muriana Stephen Nakazawa Hewitt Bakela Nare Carl Nathan Nathalie Narraidoo Sujeevi Nawaratna Kayode K Ojo Diana Ortiz Gordana Panic George Papadatos Silvia Parapini Kailash Patra Ngoc Pham Sarah Prats David M Plouffe Sally-Ann Poulsen Anupam Pradhan Celia Quevedo Ronald J Quinn Christopher A Rice Mohamed Abdo Rizk Andrea Ruecker Robert St Onge Rafaela Salgado Ferreira Jasmeet Samra Natalie G Robinett Ulrich Schlecht Marjorie Schmitt Filipe Silva Villela Francesco Silvestrini Robert Sinden Dennis A Smith Thierry Soldati Andreas Spitzmüller Serge Maximilian Stamm David J Sullivan William Sullivan Sundari Suresh Brian M Suzuki Yo Suzuki S Joshua Swamidass Donatella Taramelli Lauve R Y Tchokouaha Anjo Theron David Thomas Kathryn F Tonissen Simon Townson Abhai K Tripathi Valentin Trofimov Imran Ullah Cindy Vallieres Edgar Vigil Joseph M Vinetz Phat Voong Vinh Hoan Vu Nao-Aki Watanabe Kate Weatherby Pamela M White Andrew F Wilks Elizabeth A Winzeler Edward Wojcik Melanie Wree Wesley Wu Naoaki Yokoyama Paul H A Zollo Nada Abla Benjamin Blasco Jeremy Burrows Benoît Laleu Didier Leroy Thomas Spangenberg Timothy Wells Paul A Willis

PLoS Pathog 2016 07 28;12(7):e1005763. Epub 2016 Jul 28.

Medicines for Malaria Venture, Geneva, Switzerland.

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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July 2016
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