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

Phillips, Margaret A.; 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; 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; 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, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. 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, 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; 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.

Authors

Margaret A. Phillips

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 AVERY simon.avery@nottingham.ac.uk
Professor of Eukaryotic Microbiology

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



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.

Citation

Phillips, M. A., Van Voorhis, W. C., Adams, J. H., Adelfio, R., Ahyong, V., Akabas, M. H., …Willis, P. A. (2016). Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathogens, 12(7), https://doi.org/10.1371/journal.ppat.1005763

Journal Article Type Article
Acceptance Date Jun 21, 2016
Online Publication Date Jul 28, 2016
Publication Date Jul 28, 2016
Deposit Date Oct 19, 2016
Publicly Available Date Oct 19, 2016
Journal PLOS Pathogens
Print ISSN 1553-7366
Electronic ISSN 1553-7374
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 12
Issue 7
Article Number e1005763
DOI https://doi.org/10.1371/journal.ppat.1005763
Public URL http://eprints.nottingham.ac.uk/id/eprint/37733
Publisher URL http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005763
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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