RT Journal Article
SR Electronic
T1 Refining physico-chemical rules for herbicides using an antimalarial library
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.27.356576
DO 10.1101/2020.10.27.356576
A1 Kirill V. Sukhoverkov
A1 Maxime G. Corral
A1 Julie Leroux
A1 Joel Haywood
A1 Philipp Johnen
A1 Trevor Newton
A1 Keith A. Stubbs
A1 Joshua S. Mylne
YR 2020
UL http://biorxiv.org/content/early/2020/10/27/2020.10.27.356576.abstract
AB 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 StatementThe authors have declared no competing interest.