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Their widespread use, however, has also led to a rise in resistance and concerns about their environmental impact. Despite the need for potent and safe herbicidal molecules, no herbicide with a new mode of action has reached the market in 30\u00a0years. Although development of computational approaches has proven invaluable to guide rational drug discovery pipelines, leading to higher hit rates and lower attrition due to poor toxicity, little has been done in contrast for herbicide design. To fill this gap, we have developed cropCSM, a computational platform to help identify new, potent, nontoxic and environmentally safe herbicides. By using a knowledge-based approach, we identified physicochemical properties and substructures enriched in safe herbicides. By representing the small molecules as a graph, we leveraged these insights to guide the development of predictive models trained and tested on the largest collected data set of molecules with experimentally characterised herbicidal profiles to date (over 4500 compounds). In addition, we developed six new environmental and human toxicity predictors, spanning five different species to assist in molecule prioritisation. cropCSM was able to correctly identify 97% of herbicides currently available commercially, while predicting toxicity profiles with accuracies of up to 92%. We believe cropCSM will be an essential tool for the enrichment of screening libraries and to guide the development of potent and safe herbicides. We have made the method freely available through a user-friendly webserver at http:\/\/biosig.unimelb.edu.au\/crop_csm.<\/jats:p>","DOI":"10.1093\/bib\/bbac042","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T12:10:23Z","timestamp":1643631023000},"source":"Crossref","is-referenced-by-count":24,"title":["cropCSM: designing safe and potent herbicides with graph-based signatures"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-2119","authenticated-orcid":false,"given":"Douglas E V","family":"Pires","sequence":"first","affiliation":[{"name":"School of Computing and Information Systems at the University of Melbourne"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-402X","authenticated-orcid":false,"given":"Keith A","family":"Stubbs","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences at the University of Western Australia"}]},{"given":"Joshua S","family":"Mylne","sequence":"additional","affiliation":[{"name":"Curtin University and Deputy Director of the Centre for Crop and Disease Management"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-2413","authenticated-orcid":false,"given":"David B","family":"Ascher","sequence":"additional","affiliation":[{"name":"University of Queensland, and head of Computational Biology and Clinical Informatics at the Baker Institute and Systems"}]}],"member":"286","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"2022053123125113600_ref1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tig.2013.06.001","article-title":"Deciphering the evolution of herbicide resistance in weeds","volume":"29","author":"Delye","year":"2013","journal-title":"Trends Genet"},{"key":"2022053123125113600_ref2","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1002\/ps.4821","article-title":"The challenge of herbicide resistance around the world: a current 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