Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond

Phillips, Margaret A. and Van Voorhis, Wesley C. and Adams, John H. and Adelfio, Roberto and Ahyong, Vida and Akabas, Myles H. and Alano, Pietro and Alday, Aintzane and Alemán Resto, Yesmalie and Alsibaee, Aishah and Alzualde, Ainhoa and Andrews, Katherine T. and Avery, Simon V. and Avery, Vicky M. and Ayong, Lawrence and Baker, Mark and Baker, Stephen and Ben Mamoun, Choukri and Bhatia, Sangeeta and Bickle, Quentin and Bounaadja, Lotfi and Bowling, Tana and Bosch, Jürgen and Boucher, Lauren E. and Boyom, Fabrice F. and Brea, Jose and Brennan, Marian and Burton, Audrey and Caffrey, Conor R. and Camarda, Grazia and Carrasquilla, Manuela and Carter, Dee and Belen Cassera, Maria and Chih-Chien Cheng, Ken and Chindaudomsate, Worathad and Chubb, Anthony and Colon, Beatrice L. and Colón-López, Daisy D. and Corbett, Yolanda and Crowther, Gregory J. and Cowan, Noemi and D’Alessandro, Sarah and Le Dang, Na and Delves, Michael and DeRisi, Joseph L. and Du, Alan Y. and Duffy, Sandra and Abd El-Salam El-Sayed, Shimaa and Ferdig, Michael T. and Fernández Robledo, José A. and Fidock, David A. and Florent, Isabelle and Fokou, Patrick V. T. and Galstian, Ani and Gamo, Francisco Javier and Gokool, Suzanne and Gold, Ben and Golub, Todd and Goldgof, Gregory M. and Guha, Rajarshi and Guiguemde, W. Armand and Gural, Nil and Guy, R. Kiplin and Hansen, Michael A. E. and Hanson, Kirsten K. and Hemphill, Andrew and Hooft van Huijsduijnen, Rob and Horii, Takaaki and Horrocks, Paul and Hughes, Tyler B. and Huston, Christopher and Igarashi, Ikuo and Ingram-Sieber, Katrin and Itoe, Maurice A. and Jadhav, Ajit and Naranuntarat Jensen, Amornrat and Jensen, Laran T. and Jiang, Rays H.Y. and Kaiser, Annette and Keiser, Jennifer and Ketas, Thomas and Kicka, Sebastien and Kim, Sunyoung and Kirk, Kiaran and Kumar, Vidya P. and Kyle, Dennis E. and Lafuente, Maria Jose and Landfear, Scott and Lee, Nathan and Lee, Sukjun and Lehane, Adele M. and Li, Fengwu and Little, David and Liu, Liqiong and Llinás, Manuel and Loza, Maria I. and Lubar, Aristea and Lucantoni, Leonardo and Lucet, Isabelle and Maes, Louis and Mancama, Dalu and Mansour, Nuha R. and March, Sandra and McGowan, Sheena and Medina Vera, Iset and Meister, Stephan and Mercer, Luke and Mestres, Jordi and Mfopa, Alvine N. and Misra, Raj N. and Moon, Seunghyun and Moore, John P. and Morais Rodrigues da Costa, Francielly and Müller, Joachim and Muriana, Arantza and Nakazawa Hewitt, Stephen and Nare, Bakela and Nathan, Carl and Narraidoo, Nathalie and Nawaratna, Sujeevi and Ojo, Kayode K. and Ortiz, Diana and Panic, Gordana and Papadatos, George and Parapini, Silvia and Patra, Kailash and Pham, Ngoc and Prats, Sarah and Plouffe, David M. and Poulsen, Sally-Ann and Pradhan, Anupam and Quevedo, Celia and Quinn, Ronald J. and Rice, Christopher A. and Abdo Rizk, Mohamed and Ruecker, Andrea and St. Onge, Robert and Salgado Ferreira, Rafaela and Samra, Jasmeet and Robinett, Natalie G. and Schlecht, Ulrich and Schmitt, Marjorie and Silva Villela, Filipe and Silvestrini, Francesco and Sinden, Robert and Smith, Dennis A. and Soldati, Thierry and Spitzmüller, Andreas and Stamm, Serge Maximilian and Sullivan, David J. and Sullivan, William and Suresh, Sundari and Suzuki, Brian M. and Suzuki, Yo and Swamidass, S. Joshua and Taramelli, Donatella and Tchokouaha, Lauve R.Y. and Theron, Anjo and Thomas, David and Tonissen, Kathryn F. and Townson, Simon and Tripathi, Abhai K. and Trofimov, Valentin and Udenze, Kenneth O. and Ullah, Imran and Vallieres, Cindy and Vigil, Edgar and Vinetz, Joseph M. and Voong Vinh, Phat and Vu, Hoan and Watanabe, Nao-aki and Weatherby, Kate and White, Pamela M. and Wilks, Andrew F. and Winzeler, Elizabeth A. and Wojcik, Edward and Wree, Melanie and Wu, Wesley and Yokoyama, Naoaki and Zollo, Paul H. A. and Abla, Nada and Blasco, Benjamin and Burrows, Jeremy and Laleu, Benoît and Leroy, Didier and Spangenberg, Thomas and Wells, Timothy and Willis, Paul A. (2016) Open source drug discovery with the Malaria Box Compound collection for neglected diseases and beyond. PLOS Pathogens, 12 (7). e1005763/1-e1005763/23. ISSN 1553-7374

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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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1371/journal.ppat.1005763
Depositing User: Eprints, Support
Date Deposited: 19 Oct 2016 11:22
Last Modified: 19 Oct 2016 15:12
URI: http://eprints.nottingham.ac.uk/id/eprint/37733

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