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; 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

doi:10.1021/acscentsci.6b00086

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 DuffySabine 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

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	687-701
Number of pages	15
Journal	ACS Central Science
Volume	2
Issue number	10
Early online date	14 Sept 2016
DOIs	https://doi.org/10.1021/acscentsci.6b00086
Publication status	Published - 26 Oct 2016

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© 2016 American Chemical Society. ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.71 MBLicence: CC BY

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Williamson, A. E., Ylioja, P. M., Robertson, M. N., Antonova-Koch, Y., Avery, V., Baell, J. B., Batchu, H., Batra, S., Burrows, J. N., Bhattacharyya, S., Calderon, F., Charman, S. A., Clark, J., Crespo, B., Dean, M., Debbert, S. L., Delves, M., Dennis, A. S. M., Deroose, F., ... Todd, M. H. (2016). Open source drug discovery: highly potent antimalarial compounds derived from the Tres Cantos Arylpyrroles. ACS Central Science, 2(10), 687-701. https://doi.org/10.1021/acscentsci.6b00086

@article{afe6c0cf3eb846f1b52ff1472ed6d670,

title = "Open source drug discovery: highly potent antimalarial compounds derived from the Tres Cantos Arylpyrroles",

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.",

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

note = "Medicines for Malaria Venture (MMV), the Australian Research Council (LP120100552, LP120200557), the Australian National Health and Medical Research Council (Project Grant 1042272). G.P. and J.P.O. were supported by EMBL Member States and MMV. The characterization by NMR spectroscopy of compounds from Lawrence University was made possible by the National Science Foundation (CHE- 0923473). C.S. was supported by Wellcome Trust Biomedical Resources Grant 099156/Z/12/Z",

year = "2016",

month = oct,

day = "26",

doi = "10.1021/acscentsci.6b00086",

language = "English",

volume = "2",

pages = "687--701",

journal = "ACS Central Science",

issn = "2374-7943",

publisher = "American Chemical Society",

number = "10",

}

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

TY - JOUR

T1 - Open source drug discovery

T2 - highly potent antimalarial compounds derived from the Tres Cantos Arylpyrroles

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.

N1 - Medicines for Malaria Venture (MMV), the Australian Research Council (LP120100552, LP120200557), the Australian National Health and Medical Research Council (Project Grant 1042272). G.P. and J.P.O. were supported by EMBL Member States and MMV. The characterization by NMR spectroscopy of compounds from Lawrence University was made possible by the National Science Foundation (CHE- 0923473). C.S. was supported by Wellcome Trust Biomedical Resources Grant 099156/Z/12/Z

PY - 2016/10/26

Y1 - 2016/10/26

N2 - 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.

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.

U2 - 10.1021/acscentsci.6b00086

DO - 10.1021/acscentsci.6b00086

M3 - Article

C2 - 27800551

SN - 2374-7943

VL - 2

SP - 687

EP - 701

JO - ACS Central Science

JF - ACS Central Science

IS - 10

ER -

Open source drug discovery: highly potent antimalarial compounds derived from the Tres Cantos Arylpyrroles

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