Open source drug discovery: highly potent antimalarial compounds derived from the tres cantos arylpyrroles

Alice E Williamson, Paul M Ylioja, Murray N Robertson, Yevgeniya Antonova-Koch, Vicky Avery, Jonathan B Baell, Harikrishna Batchu, Sanjay Batra, Jeremy N Burrows, Soumya Bhattacharyya, Felix Calderon, Susan A Charman, Julie Clark, Benigno Crespo, Matin Dean, Stefan L Debbert, Michael Delves, Adelaide S M Dennis, Frederik Deroose, Sandra Duffy & 33 others Sabine Fletcher, Guri Giaever, Irene Hallyburton, Francisco-Javier Gamo, Marinella Gebbia, R Kiplin Guy, Zoe Hungerford, Kiaran Kirk, Maria J Lafuente-Monasterio, Anna Lee, Stephan Meister, Corey Nislow, John P Overington, George Papadatos, Luc Patiny, James Pham, Stuart A Ralph, Andrea Ruecker, Eileen Ryan, Christopher Southan, Kumkum Srivastava, Chris Swain, Matthew J Tarnowski, Patrick Thomson, Peter Turner, Iain M Wallace, Timothy N C Wells, Karen White, Laura White, Paul Willis, Elizabeth A Winzeler, Sergio Wittlin, Matthew H Todd

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

LanguageEnglish
Pages687-701
Number of pages15
JournalACS central science
Volume2
Issue number10
Early online date14 Sep 2016
DOIs
Publication statusPublished - 26 Oct 2016

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Antimalarials
Drug Discovery
Patents
Research
Liver
Solubility
Malaria
Assays
Esters
Lead

Keywords

  • malaria
  • antimalaria
  • drug discovery
  • large-scale phenotypic screens

Cite this

Williamson, Alice E ; Ylioja, Paul M ; Robertson, Murray N ; Antonova-Koch, Yevgeniya ; Avery, Vicky ; Baell, Jonathan B ; Batchu, Harikrishna ; Batra, Sanjay ; Burrows, Jeremy N ; Bhattacharyya, Soumya ; Calderon, Felix ; Charman, Susan A ; Clark, Julie ; Crespo, Benigno ; Dean, Matin ; Debbert, Stefan L ; Delves, Michael ; Dennis, Adelaide S M ; Deroose, Frederik ; Duffy, Sandra ; Fletcher, Sabine ; Giaever, Guri ; Hallyburton, Irene ; Gamo, Francisco-Javier ; Gebbia, Marinella ; Guy, R Kiplin ; Hungerford, Zoe ; Kirk, Kiaran ; Lafuente-Monasterio, Maria J ; Lee, Anna ; Meister, Stephan ; Nislow, Corey ; Overington, John P ; Papadatos, George ; Patiny, Luc ; Pham, James ; Ralph, Stuart A ; Ruecker, Andrea ; Ryan, Eileen ; Southan, Christopher ; Srivastava, Kumkum ; Swain, Chris ; Tarnowski, Matthew J ; Thomson, Patrick ; Turner, Peter ; Wallace, Iain M ; Wells, Timothy N C ; White, Karen ; White, Laura ; Willis, Paul ; Winzeler, Elizabeth A ; Wittlin, Sergio ; Todd, Matthew H. / Open source drug discovery : highly potent antimalarial compounds derived from the tres cantos arylpyrroles. In: ACS central science. 2016 ; Vol. 2, No. 10. pp. 687-701.
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abstract = "The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.",
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Williamson, AE, Ylioja, PM, Robertson, MN, Antonova-Koch, Y, Avery, V, Baell, JB, Batchu, H, Batra, S, Burrows, JN, Bhattacharyya, S, Calderon, F, Charman, SA, Clark, J, Crespo, B, Dean, M, Debbert, SL, Delves, M, Dennis, ASM, Deroose, F, Duffy, S, Fletcher, S, Giaever, G, Hallyburton, I, Gamo, F-J, Gebbia, M, Guy, RK, Hungerford, Z, Kirk, K, Lafuente-Monasterio, MJ, Lee, A, Meister, S, Nislow, C, Overington, JP, Papadatos, G, Patiny, L, Pham, J, Ralph, SA, Ruecker, A, Ryan, E, Southan, C, Srivastava, K, Swain, C, Tarnowski, MJ, Thomson, P, Turner, P, Wallace, IM, Wells, TNC, White, K, White, L, Willis, P, Winzeler, EA, Wittlin, S & Todd, MH 2016, 'Open source drug discovery: highly potent antimalarial compounds derived from the tres cantos arylpyrroles' ACS central science, vol. 2, no. 10, pp. 687-701. https://doi.org/10.1021/acscentsci.6b00086

Open source drug discovery : highly potent antimalarial compounds derived from the tres cantos arylpyrroles. / Williamson, Alice E; Ylioja, Paul M; Robertson, Murray N; Antonova-Koch, Yevgeniya; Avery, Vicky; Baell, Jonathan B; Batchu, Harikrishna; Batra, Sanjay; Burrows, Jeremy N; Bhattacharyya, Soumya; Calderon, Felix; Charman, Susan A; Clark, Julie; Crespo, Benigno; Dean, Matin; Debbert, Stefan L; Delves, Michael; Dennis, Adelaide S M; Deroose, Frederik; Duffy, Sandra; Fletcher, Sabine; Giaever, Guri; Hallyburton, Irene; Gamo, Francisco-Javier; Gebbia, Marinella; Guy, R Kiplin; Hungerford, Zoe; Kirk, Kiaran; Lafuente-Monasterio, Maria J; Lee, Anna; Meister, Stephan; Nislow, Corey; Overington, John P; Papadatos, George; Patiny, Luc; Pham, James; Ralph, Stuart A; Ruecker, Andrea; Ryan, Eileen; Southan, Christopher; Srivastava, Kumkum; Swain, Chris; Tarnowski, Matthew J; Thomson, Patrick; Turner, Peter; Wallace, Iain M; Wells, Timothy N C; White, Karen; White, Laura; Willis, Paul; Winzeler, Elizabeth A; Wittlin, Sergio; Todd, Matthew H.

In: ACS central science, Vol. 2, No. 10, 26.10.2016, p. 687-701.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Open source drug discovery

T2 - ACS central science

AU - Williamson, Alice E

AU - Ylioja, Paul M

AU - Robertson, Murray N

AU - Antonova-Koch, Yevgeniya

AU - Avery, Vicky

AU - Baell, Jonathan B

AU - Batchu, Harikrishna

AU - Batra, Sanjay

AU - Burrows, Jeremy N

AU - Bhattacharyya, Soumya

AU - Calderon, Felix

AU - Charman, Susan A

AU - Clark, Julie

AU - Crespo, Benigno

AU - Dean, Matin

AU - Debbert, Stefan L

AU - Delves, Michael

AU - Dennis, Adelaide S M

AU - Deroose, Frederik

AU - Duffy, Sandra

AU - Fletcher, Sabine

AU - Giaever, Guri

AU - Hallyburton, Irene

AU - Gamo, Francisco-Javier

AU - Gebbia, Marinella

AU - Guy, R Kiplin

AU - Hungerford, Zoe

AU - Kirk, Kiaran

AU - Lafuente-Monasterio, Maria J

AU - Lee, Anna

AU - Meister, Stephan

AU - Nislow, Corey

AU - Overington, John P

AU - Papadatos, George

AU - Patiny, Luc

AU - Pham, James

AU - Ralph, Stuart A

AU - Ruecker, Andrea

AU - Ryan, Eileen

AU - Southan, Christopher

AU - Srivastava, Kumkum

AU - Swain, Chris

AU - Tarnowski, Matthew J

AU - Thomson, Patrick

AU - Turner, Peter

AU - Wallace, Iain M

AU - Wells, Timothy N C

AU - White, Karen

AU - White, Laura

AU - Willis, Paul

AU - Winzeler, Elizabeth A

AU - Wittlin, Sergio

AU - Todd, Matthew H

PY - 2016/10/26

Y1 - 2016/10/26

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AB - The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

KW - malaria

KW - antimalaria

KW - drug discovery

KW - large-scale phenotypic screens

U2 - 10.1021/acscentsci.6b00086

DO - 10.1021/acscentsci.6b00086

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VL - 2

SP - 687

EP - 701

JO - ACS central science

JF - ACS central science

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