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

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 N Bhatia, Quentin Bickle, Lotfi Bounaadja & 167 others 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 J 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-Benito, Suzanne Gokool, Ben Gold, Todd Golub, Gregory M. Goldgof, Rajarshi Guha, Wendyam 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-Riera, 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 E 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

Research output: Contribution to journalArticleResearchpeer-review

93 Citations (Scopus)

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.

Original languageEnglish
Article numbere1005763
Number of pages23
JournalPLoS Pathogens
Volume12
Issue number7
DOIs
Publication statusPublished - 28 Jul 2016

Keywords

  • malaria
  • malarial parasites
  • plasmodium
  • gametocytes
  • drug discovery
  • drug metabolism
  • toxicity
  • medicinal chemistry

Cite this

Van Voorhis, W. C., Adams, J. H., Adelfio, R., Ahyong, V., Akabas, M. H., Alano, P., ... Willis, P. A. (2016). Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathogens, 12(7), [e1005763]. https://doi.org/10.1371/journal.ppat.1005763
Van Voorhis, Wesley C. ; Adams, John H. ; Adelfio, Roberto ; Ahyong, Vida ; Akabas, Myles H. ; Alano, Pietro ; Alday, Aintzane ; Alemán Resto, Yesmalie ; Alsibaee, Aishah ; Alzualde, Ainhoa ; Andrews, Katherine T ; Avery, Simon V. ; Avery, Vicky M ; Ayong, Lawrence ; Baker, Mark ; Baker, Stephen ; Ben Mamoun, Choukri ; Bhatia, Sangeeta N ; Bickle, Quentin ; Bounaadja, Lotfi ; Bowling, Tana ; Bosch, Jürgen ; Boucher, Lauren E. ; Boyom, Fabrice F. ; Brea, Jose ; Brennan, Marian ; Burton, Audrey ; Caffrey, Conor R ; Camarda, Grazia ; Carrasquilla, Manuela ; Carter, Dee ; Belen Cassera, Maria ; Chih-Chien Cheng, Ken ; Chindaudomsate, Worathad ; Chubb, Anthony ; Colon, Beatrice L. ; Colón-López, Daisy D. ; Corbett, Yolanda ; Crowther, Gregory J. ; Cowan, Noemi ; D’Alessandro, Sarah ; Le Dang, Na ; Delves, Michael J ; DeRisi, Joseph L. ; Du, Alan Y. ; Duffy, Sandra ; Abd El-Salam El-Sayed, Shimaa ; Ferdig, Michael T. ; Fernández Robledo, José A. ; Fidock, David A ; Florent, Isabelle ; Fokou, Patrick V.T. ; Galstian, Ani ; Gamo-Benito, Francisco Javier ; Gokool, Suzanne ; Gold, Ben ; Golub, Todd ; Goldgof, Gregory M. ; Guha, Rajarshi ; Guiguemde, Wendyam Armand ; Gural, Nil ; Guy, R Kiplin ; Hansen, Michael A.E. ; Hanson, Kirsten K. ; Hemphill, Andrew ; Hooft van Huijsduijnen, Rob ; Horii, Takaaki ; Horrocks, Paul ; Hughes, Tyler B. ; Huston, Christopher ; Igarashi, Ikuo ; Ingram-Sieber, Katrin ; Itoe, Maurice A. ; Jadhav, Ajit ; Naranuntarat Jensen, Amornrat ; Jensen, Laran T. ; Jiang, Rays H.Y. ; Kaiser, Annette ; Keiser, Jennifer ; Ketas, Thomas ; Kicka, Sebastien ; Kim, Sunyoung ; Kirk, Kiaran ; Kumar, Vidya P. ; Kyle, Dennis E ; Lafuente, Maria Jose ; Landfear, Scott ; Lee, Nathan ; Lee, Sukjun ; Lehane, Adele M ; Li, Fengwu ; Little, David ; Liu, Liqiong ; Llinás, Manuel ; Loza, Maria I. ; Lubar, Aristea ; Lucantoni, Leonardo ; Lucet, Isabelle ; Maes, Louis ; Mancama, Dalu ; Mansour, Nuha R. ; March-Riera, Sandra ; McGowan, Sheena ; Medina Vera, Iset ; Meister, Stephan ; Mercer, Luke ; Mestres, Jordi ; Mfopa, Alvine N. ; Misra, Raj N. ; Moon, Seunghyun ; Moore, John P ; Morais Rodrigues da Costa, Francielly ; Müller, Joachim ; Muriana, Arantza ; Nakazawa Hewitt, Stephen ; Nare, Bakela ; Nathan, Carl ; Narraidoo, Nathalie ; Nawaratna, Sujeevi ; Ojo, Kayode K. ; Ortiz, Diana ; Panic, Gordana ; Papadatos, George ; Parapini, Silvia ; Patra, Kailash ; Pham, Ngoc ; Prats, Sarah ; Plouffe, David M. ; Poulsen, Sally-Ann ; Pradhan, Anupam ; Quevedo, Celia ; Quinn, Ronald J ; Rice, Christopher A. ; Abdo Rizk, Mohamed ; Ruecker, Andrea ; St. Onge, Robert ; Salgado Ferreira, Rafaela ; Samra, Jasmeet ; Robinett, Natalie G. ; Schlecht, Ulrich ; Schmitt, Marjorie ; Silva Villela, Filipe ; Silvestrini, Francesco ; Sinden, Robert E ; Smith, Dennis A. ; Soldati, Thierry ; Spitzmüller, Andreas ; Stamm, Serge Maximilian ; Sullivan, David J. ; Sullivan, William ; Suresh, Sundari ; Suzuki, Brian M. ; Suzuki, Yo ; Swamidass, S. Joshua ; Taramelli, Donatella ; Tchokouaha, Lauve R.Y. ; 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 ; Voong Vinh, Phat ; Vu, Hoan ; Watanabe, Nao Aki ; Weatherby, Kate ; White, Pamela M. ; Wilks, Andrew F. ; Winzeler, Elizabeth A. ; Wojcik, Edward ; Wree, Melanie ; Wu, Wesley ; Yokoyama, Naoaki ; Zollo, Paul H.A. ; Abla, Nada ; Blasco, Benjamin ; Burrows, Jeremy ; Laleu, Benoît ; Leroy, Didier ; Spangenberg, Thomas ; Wells, Timothy ; Willis, Paul A. / Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. In: PLoS Pathogens. 2016 ; Vol. 12, No. 7.
@article{686d358d5b994ac9b9fe34e5bf48d0b3,
title = "Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond",
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.",
keywords = "malaria, malarial parasites, plasmodium, gametocytes, drug discovery, drug metabolism, toxicity, medicinal chemistry",
author = "{Van Voorhis}, {Wesley C.} and Adams, {John H.} and Roberto Adelfio and Vida Ahyong and Akabas, {Myles H.} and Pietro Alano and Aintzane Alday and {Alem{\'a}n Resto}, Yesmalie and Aishah Alsibaee and Ainhoa Alzualde and Andrews, {Katherine T} and Avery, {Simon V.} and Avery, {Vicky M} and Lawrence Ayong and Mark Baker and Stephen Baker and {Ben Mamoun}, Choukri and Bhatia, {Sangeeta N} and Quentin Bickle and Lotfi Bounaadja and Tana Bowling and J{\"u}rgen Bosch and Boucher, {Lauren E.} and Boyom, {Fabrice F.} and Jose Brea and Marian Brennan and Audrey Burton and Caffrey, {Conor R} and Grazia Camarda and Manuela Carrasquilla and Dee Carter and {Belen Cassera}, Maria and {Chih-Chien Cheng}, Ken and Worathad Chindaudomsate and Anthony Chubb and Colon, {Beatrice L.} and Col{\'o}n-L{\'o}pez, {Daisy D.} and Yolanda Corbett and Crowther, {Gregory J.} and Noemi Cowan and Sarah D’Alessandro and {Le Dang}, Na and Delves, {Michael J} and DeRisi, {Joseph L.} and Du, {Alan Y.} and Sandra Duffy and {Abd El-Salam El-Sayed}, Shimaa and Ferdig, {Michael T.} and {Fern{\'a}ndez Robledo}, {Jos{\'e} A.} and Fidock, {David A} and Isabelle Florent and Fokou, {Patrick V.T.} and Ani Galstian and Gamo-Benito, {Francisco Javier} and Suzanne Gokool and Ben Gold and Todd Golub and Goldgof, {Gregory M.} and Rajarshi Guha and Guiguemde, {Wendyam Armand} and Nil Gural and Guy, {R Kiplin} and Hansen, {Michael A.E.} and Hanson, {Kirsten K.} and Andrew Hemphill and {Hooft van Huijsduijnen}, Rob and Takaaki Horii and Paul Horrocks and Hughes, {Tyler B.} and Christopher Huston and Ikuo Igarashi and Katrin Ingram-Sieber and Itoe, {Maurice A.} and Ajit Jadhav and {Naranuntarat Jensen}, Amornrat and Jensen, {Laran T.} and Jiang, {Rays H.Y.} and Annette Kaiser and Jennifer Keiser and Thomas Ketas and Sebastien Kicka and Sunyoung Kim and Kiaran Kirk and Kumar, {Vidya P.} and Kyle, {Dennis E} and Lafuente, {Maria Jose} and Scott Landfear and Nathan Lee and Sukjun Lee and Lehane, {Adele M} and Fengwu Li and David Little and Liqiong Liu and Manuel Llin{\'a}s and Loza, {Maria I.} and Aristea Lubar and Leonardo Lucantoni and Isabelle Lucet and Louis Maes and Dalu Mancama and Mansour, {Nuha R.} and Sandra March-Riera and Sheena McGowan and {Medina Vera}, Iset and Stephan Meister and Luke Mercer and Jordi Mestres and Mfopa, {Alvine N.} and Misra, {Raj N.} and Seunghyun Moon and Moore, {John P} and {Morais Rodrigues da Costa}, Francielly and Joachim M{\"u}ller and Arantza Muriana and {Nakazawa Hewitt}, Stephen and Bakela Nare and Carl Nathan and Nathalie Narraidoo and Sujeevi Nawaratna and Ojo, {Kayode K.} and Diana Ortiz and Gordana Panic and George Papadatos and Silvia Parapini and Kailash Patra and Ngoc Pham and Sarah Prats and Plouffe, {David M.} and Sally-Ann Poulsen and Anupam Pradhan and Celia Quevedo and Quinn, {Ronald J} and Rice, {Christopher A.} and {Abdo Rizk}, Mohamed and Andrea Ruecker and {St. Onge}, Robert and {Salgado Ferreira}, Rafaela and Jasmeet Samra and Robinett, {Natalie G.} and Ulrich Schlecht and Marjorie Schmitt and {Silva Villela}, Filipe and Francesco Silvestrini and Sinden, {Robert E} and Smith, {Dennis A.} and Thierry Soldati and Andreas Spitzm{\"u}ller and Stamm, {Serge Maximilian} and Sullivan, {David J.} and William Sullivan and Sundari Suresh and Suzuki, {Brian M.} and Yo Suzuki and Swamidass, {S. Joshua} and Donatella Taramelli and Tchokouaha, {Lauve R.Y.} and Anjo Theron and David Thomas and Tonissen, {Kathryn F.} and Simon Townson and Tripathi, {Abhai K.} and Valentin Trofimov and Udenze, {Kenneth O.} and Imran Ullah and Cindy Vallieres and Edgar Vigil and Vinetz, {Joseph M} and {Voong Vinh}, Phat and Hoan Vu and Watanabe, {Nao Aki} and Kate Weatherby and White, {Pamela M.} and Wilks, {Andrew F.} and Winzeler, {Elizabeth A.} and Edward Wojcik and Melanie Wree and Wesley Wu and Naoaki Yokoyama and Zollo, {Paul H.A.} and Nada Abla and Benjamin Blasco and Jeremy Burrows and Beno{\^i}t Laleu and Didier Leroy and Thomas Spangenberg and Timothy Wells and Willis, {Paul A.}",
year = "2016",
month = "7",
day = "28",
doi = "10.1371/journal.ppat.1005763",
language = "English",
volume = "12",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "7",

}

Van Voorhis, WC, Adams, JH, Adelfio, R, Ahyong, V, Akabas, MH, Alano, P, Alday, A, Alemán Resto, Y, Alsibaee, A, Alzualde, A, Andrews, KT, Avery, SV, Avery, VM, Ayong, L, Baker, M, Baker, S, Ben Mamoun, C, Bhatia, SN, Bickle, Q, Bounaadja, L, Bowling, T, Bosch, J, Boucher, LE, Boyom, FF, Brea, J, Brennan, M, Burton, A, Caffrey, CR, Camarda, G, Carrasquilla, M, Carter, D, Belen Cassera, M, Chih-Chien Cheng, K, Chindaudomsate, W, Chubb, A, Colon, BL, Colón-López, DD, Corbett, Y, Crowther, GJ, Cowan, N, D’Alessandro, S, Le Dang, N, Delves, MJ, DeRisi, JL, Du, AY, Duffy, S, Abd El-Salam El-Sayed, S, Ferdig, MT, Fernández Robledo, JA, Fidock, DA, Florent, I, Fokou, PVT, Galstian, A, Gamo-Benito, FJ, Gokool, S, Gold, B, Golub, T, Goldgof, GM, Guha, R, Guiguemde, WA, Gural, N, Guy, RK, Hansen, MAE, Hanson, KK, Hemphill, A, Hooft van Huijsduijnen, R, Horii, T, Horrocks, P, Hughes, TB, Huston, C, Igarashi, I, Ingram-Sieber, K, Itoe, MA, Jadhav, A, Naranuntarat Jensen, A, Jensen, LT, Jiang, RHY, Kaiser, A, Keiser, J, Ketas, T, Kicka, S, Kim, S, Kirk, K, Kumar, VP, Kyle, DE, Lafuente, MJ, Landfear, S, Lee, N, Lee, S, Lehane, AM, Li, F, Little, D, Liu, L, Llinás, M, Loza, MI, Lubar, A, Lucantoni, L, Lucet, I, Maes, L, Mancama, D, Mansour, NR, March-Riera, S, McGowan, S, Medina Vera, I, Meister, S, Mercer, L, Mestres, J, Mfopa, AN, Misra, RN, Moon, S, Moore, JP, Morais Rodrigues da Costa, F, Müller, J, Muriana, A, Nakazawa Hewitt, S, Nare, B, Nathan, C, Narraidoo, N, Nawaratna, S, Ojo, KK, Ortiz, D, Panic, G, Papadatos, G, Parapini, S, Patra, K, Pham, N, Prats, S, Plouffe, DM, Poulsen, S-A, Pradhan, A, Quevedo, C, Quinn, RJ, Rice, CA, Abdo Rizk, M, Ruecker, A, St. Onge, R, Salgado Ferreira, R, Samra, J, Robinett, NG, Schlecht, U, Schmitt, M, Silva Villela, F, Silvestrini, F, Sinden, RE, Smith, DA, Soldati, T, Spitzmüller, A, Stamm, SM, Sullivan, DJ, Sullivan, W, Suresh, S, Suzuki, BM, Suzuki, Y, Swamidass, SJ, Taramelli, D, Tchokouaha, LRY, Theron, A, Thomas, D, Tonissen, KF, Townson, S, Tripathi, AK, Trofimov, V, Udenze, KO, Ullah, I, Vallieres, C, Vigil, E, Vinetz, JM, Voong Vinh, P, Vu, H, Watanabe, NA, Weatherby, K, White, PM, Wilks, AF, Winzeler, EA, Wojcik, E, Wree, M, Wu, W, Yokoyama, N, Zollo, PHA, Abla, N, Blasco, B, Burrows, J, Laleu, B, Leroy, D, Spangenberg, T, Wells, T & Willis, PA 2016, 'Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond', PLoS Pathogens, vol. 12, no. 7, e1005763. https://doi.org/10.1371/journal.ppat.1005763

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

In: PLoS Pathogens, Vol. 12, No. 7, e1005763, 28.07.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

AU - Van Voorhis, Wesley C.

AU - Adams, John H.

AU - Adelfio, Roberto

AU - Ahyong, Vida

AU - Akabas, Myles H.

AU - Alano, Pietro

AU - Alday, Aintzane

AU - Alemán Resto, Yesmalie

AU - Alsibaee, Aishah

AU - Alzualde, Ainhoa

AU - Andrews, Katherine T

AU - Avery, Simon V.

AU - Avery, Vicky M

AU - Ayong, Lawrence

AU - Baker, Mark

AU - Baker, Stephen

AU - Ben Mamoun, Choukri

AU - Bhatia, Sangeeta N

AU - Bickle, Quentin

AU - Bounaadja, Lotfi

AU - Bowling, Tana

AU - Bosch, Jürgen

AU - Boucher, Lauren E.

AU - Boyom, Fabrice F.

AU - Brea, Jose

AU - Brennan, Marian

AU - Burton, Audrey

AU - Caffrey, Conor R

AU - Camarda, Grazia

AU - Carrasquilla, Manuela

AU - Carter, Dee

AU - Belen Cassera, Maria

AU - Chih-Chien Cheng, Ken

AU - Chindaudomsate, Worathad

AU - Chubb, Anthony

AU - Colon, Beatrice L.

AU - Colón-López, Daisy D.

AU - Corbett, Yolanda

AU - Crowther, Gregory J.

AU - Cowan, Noemi

AU - D’Alessandro, Sarah

AU - Le Dang, Na

AU - Delves, Michael J

AU - DeRisi, Joseph L.

AU - Du, Alan Y.

AU - Duffy, Sandra

AU - Abd El-Salam El-Sayed, Shimaa

AU - Ferdig, Michael T.

AU - Fernández Robledo, José A.

AU - Fidock, David A

AU - Florent, Isabelle

AU - Fokou, Patrick V.T.

AU - Galstian, Ani

AU - Gamo-Benito, Francisco Javier

AU - Gokool, Suzanne

AU - Gold, Ben

AU - Golub, Todd

AU - Goldgof, Gregory M.

AU - Guha, Rajarshi

AU - Guiguemde, Wendyam Armand

AU - Gural, Nil

AU - Guy, R Kiplin

AU - Hansen, Michael A.E.

AU - Hanson, Kirsten K.

AU - Hemphill, Andrew

AU - Hooft van Huijsduijnen, Rob

AU - Horii, Takaaki

AU - Horrocks, Paul

AU - Hughes, Tyler B.

AU - Huston, Christopher

AU - Igarashi, Ikuo

AU - Ingram-Sieber, Katrin

AU - Itoe, Maurice A.

AU - Jadhav, Ajit

AU - Naranuntarat Jensen, Amornrat

AU - Jensen, Laran T.

AU - Jiang, Rays H.Y.

AU - Kaiser, Annette

AU - Keiser, Jennifer

AU - Ketas, Thomas

AU - Kicka, Sebastien

AU - Kim, Sunyoung

AU - Kirk, Kiaran

AU - Kumar, Vidya P.

AU - Kyle, Dennis E

AU - Lafuente, Maria Jose

AU - Landfear, Scott

AU - Lee, Nathan

AU - Lee, Sukjun

AU - Lehane, Adele M

AU - Li, Fengwu

AU - Little, David

AU - Liu, Liqiong

AU - Llinás, Manuel

AU - Loza, Maria I.

AU - Lubar, Aristea

AU - Lucantoni, Leonardo

AU - Lucet, Isabelle

AU - Maes, Louis

AU - Mancama, Dalu

AU - Mansour, Nuha R.

AU - March-Riera, Sandra

AU - McGowan, Sheena

AU - Medina Vera, Iset

AU - Meister, Stephan

AU - Mercer, Luke

AU - Mestres, Jordi

AU - Mfopa, Alvine N.

AU - Misra, Raj N.

AU - Moon, Seunghyun

AU - Moore, John P

AU - Morais Rodrigues da Costa, Francielly

AU - Müller, Joachim

AU - Muriana, Arantza

AU - Nakazawa Hewitt, Stephen

AU - Nare, Bakela

AU - Nathan, Carl

AU - Narraidoo, Nathalie

AU - Nawaratna, Sujeevi

AU - Ojo, Kayode K.

AU - Ortiz, Diana

AU - Panic, Gordana

AU - Papadatos, George

AU - Parapini, Silvia

AU - Patra, Kailash

AU - Pham, Ngoc

AU - Prats, Sarah

AU - Plouffe, David M.

AU - Poulsen, Sally-Ann

AU - Pradhan, Anupam

AU - Quevedo, Celia

AU - Quinn, Ronald J

AU - Rice, Christopher A.

AU - Abdo Rizk, Mohamed

AU - Ruecker, Andrea

AU - St. Onge, Robert

AU - Salgado Ferreira, Rafaela

AU - Samra, Jasmeet

AU - Robinett, Natalie G.

AU - Schlecht, Ulrich

AU - Schmitt, Marjorie

AU - Silva Villela, Filipe

AU - Silvestrini, Francesco

AU - Sinden, Robert E

AU - Smith, Dennis A.

AU - Soldati, Thierry

AU - Spitzmüller, Andreas

AU - Stamm, Serge Maximilian

AU - Sullivan, David J.

AU - Sullivan, William

AU - Suresh, Sundari

AU - Suzuki, Brian M.

AU - Suzuki, Yo

AU - Swamidass, S. Joshua

AU - Taramelli, Donatella

AU - Tchokouaha, Lauve R.Y.

AU - Theron, Anjo

AU - Thomas, David

AU - Tonissen, Kathryn F.

AU - Townson, Simon

AU - Tripathi, Abhai K.

AU - Trofimov, Valentin

AU - Udenze, Kenneth O.

AU - Ullah, Imran

AU - Vallieres, Cindy

AU - Vigil, Edgar

AU - Vinetz, Joseph M

AU - Voong Vinh, Phat

AU - Vu, Hoan

AU - Watanabe, Nao Aki

AU - Weatherby, Kate

AU - White, Pamela M.

AU - Wilks, Andrew F.

AU - Winzeler, Elizabeth A.

AU - Wojcik, Edward

AU - Wree, Melanie

AU - Wu, Wesley

AU - Yokoyama, Naoaki

AU - Zollo, Paul H.A.

AU - Abla, Nada

AU - Blasco, Benjamin

AU - Burrows, Jeremy

AU - Laleu, Benoît

AU - Leroy, Didier

AU - Spangenberg, Thomas

AU - Wells, Timothy

AU - Willis, Paul A.

PY - 2016/7/28

Y1 - 2016/7/28

N2 - 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.

AB - 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.

KW - malaria

KW - malarial parasites

KW - plasmodium

KW - gametocytes

KW - drug discovery

KW - drug metabolism

KW - toxicity

KW - medicinal chemistry

UR - http://www.scopus.com/inward/record.url?scp=84982980463&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1005763

DO - 10.1371/journal.ppat.1005763

M3 - Article

VL - 12

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 7

M1 - e1005763

ER -

Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P et al. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathogens. 2016 Jul 28;12(7). e1005763. https://doi.org/10.1371/journal.ppat.1005763