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

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)687-701
Number of pages15
JournalACS Central Science
Volume2
Issue number10
Early online date14 Sep 2016
DOIs
Publication statusPublished - 26 Oct 2016

Keywords

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

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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