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

• Main 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, 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, Kenneth O Udenze, 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
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2016-07-01
• Series: PLoS Pathogens
• Online Access: https://doi.org/10.1371/journal.ppat.1005763

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.