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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Journal:
PLoS pathogens, Volume: 12, Issue: 7
Published:
July 28, 2016
PMID:
27467575
Authors:
Wesley C Van Voorhis WC, John H Adams JH, Roberto Adelfio R, Vida Ahyong V, Myles H Akabas MH, Pietro Alano P, Aintzane Alday A, Yesmalie Alemán Resto Y, Aishah Alsibaee A, Ainhoa Alzualde A, Katherine T Andrews KT, Simon V Avery SV, Vicky M Avery VM, Lawrence Ayong L, Mark Baker M, Stephen Baker S, Choukri Ben Mamoun C, Sangeeta Bhatia S, Quentin Bickle Q, Lotfi Bounaadja L, Tana Bowling T, Jürgen Bosch J, Lauren E Boucher LE, Fabrice F Boyom FF, Jose Brea J, Marian Brennan M, Audrey Burton A, Conor R Caffrey CR, Grazia Camarda G, Manuela Carrasquilla M, Dee Carter D, Maria Belen Cassera M, Ken Chih-Chien Cheng K, Worathad Chindaudomsate W, Anthony Chubb A, Beatrice L Colon BL, Daisy D Colón-López DD, Yolanda Corbett Y, Gregory J Crowther GJ, Noemi Cowan N, Sarah D'Alessandro S, Na Le Dang N, Michael Delves M, Joseph L DeRisi JL, Alan Y Du AY, Sandra Duffy S, Shimaa Abd El-Salam El-Sayed S, Michael T Ferdig MT, José A Fernández Robledo JA, David A Fidock DA, Isabelle Florent I, Patrick V T Fokou PV, Ani Galstian A, Francisco Javier Gamo FJ, Suzanne Gokool S, Ben Gold B, Todd Golub T, Gregory M Goldgof GM, Rajarshi Guha R, W Armand Guiguemde WA, Nil Gural N, R Kiplin Guy RK, Michael A E Hansen MA, Kirsten K Hanson KK, Andrew Hemphill A, Rob Hooft van Huijsduijnen R, Takaaki Horii T, Paul Horrocks P, Tyler B Hughes TB, Christopher Huston C, Ikuo Igarashi I, Katrin Ingram-Sieber K, Maurice A Itoe MA, Ajit Jadhav A, Amornrat Naranuntarat Jensen A, Laran T Jensen LT, Rays H Y Jiang RH, Annette Kaiser A, Jennifer Keiser J, Thomas Ketas T, Sebastien Kicka S, Sunyoung Kim S, Kiaran Kirk K, Vidya P Kumar VP, Dennis E Kyle DE, Maria Jose Lafuente MJ, Scott Landfear S, Nathan Lee N, Sukjun Lee S, Adele M Lehane AM, Fengwu Li F, David Little D, Liqiong Liu L, Manuel Llinás M, Maria I Loza MI, Aristea Lubar A, Leonardo Lucantoni L, Isabelle Lucet I, Louis Maes L, Dalu Mancama D, Nuha R Mansour NR, Sandra March S, Sheena McGowan S, Iset Medina Vera I, Stephan Meister S, Luke Mercer L, Jordi Mestres J, Alvine N Mfopa AN, Raj N Misra RN, Seunghyun Moon S, John P Moore JP, Francielly Morais Rodrigues da Costa F, Joachim Müller J, Arantza Muriana A, Stephen Nakazawa Hewitt S, Bakela Nare B, Carl Nathan C, Nathalie Narraidoo N, Sujeevi Nawaratna S, Kayode K Ojo KK, Diana Ortiz D, Gordana Panic G, George Papadatos G, Silvia Parapini S, Kailash Patra K, Ngoc Pham N, Sarah Prats S, David M Plouffe DM, Sally-Ann Poulsen SA, Anupam Pradhan A, Celia Quevedo C, Ronald J Quinn RJ, Christopher A Rice CA, Mohamed Abdo Rizk M, Andrea Ruecker A, Robert St Onge R, Rafaela Salgado Ferreira R, Jasmeet Samra J, Natalie G Robinett NG, Ulrich Schlecht U, Marjorie Schmitt M, Filipe Silva Villela F, Francesco Silvestrini F, Robert Sinden R, Dennis A Smith DA, Thierry Soldati T, Andreas Spitzmüller A, Serge Maximilian Stamm SM, David J Sullivan DJ, William Sullivan W, Sundari Suresh S, Brian M Suzuki BM, Yo Suzuki Y, S Joshua Swamidass SJ, Donatella Taramelli D, Lauve R Y Tchokouaha LR, Anjo Theron A, David Thomas D, Kathryn F Tonissen KF, Simon Townson S, Abhai K Tripathi AK, Valentin Trofimov V, Kenneth O Udenze KO, Imran Ullah I, Cindy Vallieres C, Edgar Vigil E, Joseph M Vinetz JM, Phat Voong Vinh P, Hoan Vu H, Nao-Aki Watanabe NA, Kate Weatherby K, Pamela M White PM, Andrew F Wilks AF, Elizabeth A Winzeler EA, Edward Wojcik E, Melanie Wree M, Wesley Wu W, Naoaki Yokoyama N, Paul H A Zollo PH, Nada Abla N, Benjamin Blasco B, Jeremy Burrows J, Benoît Laleu B, Didier Leroy D, Thomas Spangenberg T, Timothy Wells T, Paul A Willis PA
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.