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Refining physico-chemical rules for herbicides using an antimalarial library

View ORCID ProfileKirill V. Sukhoverkov, View ORCID ProfileMaxime G. Corral, Julie Leroux, View ORCID ProfileJoel Haywood, Philipp Johnen, Trevor Newton, View ORCID ProfileKeith A. Stubbs, View ORCID ProfileJoshua S. Mylne
doi: https://doi.org/10.1101/2020.10.27.356576
Kirill V. Sukhoverkov
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The University of Western Australia, The ARC Centre of Excellence in Plant Energy Biology, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Maxime G. Corral
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The University of Western Australia, The ARC Centre of Excellence in Plant Energy Biology, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Julie Leroux
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The University of Western Australia, The ARC Centre of Excellence in Plant Energy Biology, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Joel Haywood
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The University of Western Australia, The ARC Centre of Excellence in Plant Energy Biology, 35 Stirling Highway, Crawley, Perth 6009, Australia
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Philipp Johnen
3BASF SE, Speyerer Straße 2, 67117 Limburgerhof, Germany
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Trevor Newton
3BASF SE, Speyerer Straße 2, 67117 Limburgerhof, Germany
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Keith A. Stubbs
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
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  • For correspondence: joshua.mylne@uwa.edu.au keith.stubbs@uwa.edu.au
Joshua S. Mylne
1The University of Western Australia, School of Molecular Sciences, 35 Stirling Highway, Crawley, Perth 6009, Australia
2The University of Western Australia, The ARC Centre of Excellence in Plant Energy Biology, 35 Stirling Highway, Crawley, Perth 6009, Australia
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  • For correspondence: joshua.mylne@uwa.edu.au keith.stubbs@uwa.edu.au
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ABSTRACT

Successful herbicides, like drugs, have physico-chemical properties that usually fall within certain limits. A recent analysis of 334 herbicides showed similar properties to the ‘rule of five’ for human orally-delivered drugs, but herbicides diverged from this for proton donors, partition coefficients and molecular weight. To refine rules for herbicides, we exploited the close evolutionary relationship between P. falciparum and plants by screening the Malaria Box, a 400-compound library composed of novel chemical scaffolds with activity against blood stage malaria parasite Plasmodium falciparum. A high proportion (52 of 400) were herbicidal to Arabidopsis thaliana on agar plates. Thirty-nine of these 52 herbicidal compounds were tested on soil and 16 compounds were herbicidal. These data were used to predict whether a herbicidal hit found on agar will work on soil-grown plants. The physico-chemical parameters were weighted to logP and formal charge and used to generate weighted scores to a large chemical library of liver-stage effective antimalarial leads. Of the six top-scoring compounds, one had a potency comparable to commercial herbicides. This novel compound MMV1206386 had no close structural matches among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 27, 2020.
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Refining physico-chemical rules for herbicides using an antimalarial library
Kirill V. Sukhoverkov, Maxime G. Corral, Julie Leroux, Joel Haywood, Philipp Johnen, Trevor Newton, Keith A. Stubbs, Joshua S. Mylne
bioRxiv 2020.10.27.356576; doi: https://doi.org/10.1101/2020.10.27.356576
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Refining physico-chemical rules for herbicides using an antimalarial library
Kirill V. Sukhoverkov, Maxime G. Corral, Julie Leroux, Joel Haywood, Philipp Johnen, Trevor Newton, Keith A. Stubbs, Joshua S. Mylne
bioRxiv 2020.10.27.356576; doi: https://doi.org/10.1101/2020.10.27.356576

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