title: In silico target prediction for elucidating the mode of action of herbicides including prospective validation.
abstract: The rapid emergence of pesticide resistance has given rise to a demand for herbicides with new mode of action (MoA). In the agrochemical sector, with the availability of experimental high throughput screening (HTS) data, it is now possible to utilize in silico target prediction methods in the early discovery phase to suggest the MoA of a compound via data mining of bioactivity data. While having been established in the pharmaceutical context, in the agrochemical area this approach poses rather different challenges, as we have found in this work, partially due to different chemistry, but even more so due to different (usually smaller) amounts of data, and different ways of conducting HTS. With the aim to apply computational methods for facilitating herbicide target identification, 48,000 bioactivity data against 16 herbicide targets were processed to train Laplacian modified Naïve Bayesian (NB) classification models. The herbicide target prediction model ("HerbiMod") is an ensemble of 16 binary classification models which are evaluated by internal, external and prospective validation sets. In addition to the experimental inactives, 10,000 random agrochemical inactives were included in the training process, which showed to improve the overall balanced accuracy of our models up to 40%. For all the models, performance in terms of balanced accuracy of≥80% was achieved in five-fold cross validation. Ranking target predictions was addressed by means of z-scores which improved predictivity over using raw scores alone. An external testset of 247 compounds from ChEMBL and a prospective testset of 394 compounds from BASF SE tested against five well studied herbicide targets (ACC, ALS, HPPD, PDS and PROTOX) were used for further validation. Only 4% of the compounds in the external testset lied in the applicability domain and extrapolation (and correct prediction) was hence impossible, which on one hand was surprising, and on the other hand illustrated the utilization of using applicability domains in the first place. However, performance better than 60% in balanced accuracy was achieved on the prospective testset, where all the compounds fell within the applicability domain, and which hence underlines the possibility of using target prediction also in the area of agrochemicals.
authors.affiliation: Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Rucha K
authors.initials: RK
authors.lastname: Chiddarwar
authors.affiliation: Global Research Crop Protection, BASF SE, Speyerer Strasse 2, 67177 Limburgerhof, Germany.
authors.forename: Sebastian G
authors.initials: SG
authors.lastname: Rohrer
authors.affiliation: Computational Chemistry and Biology, BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Global Research Crop Protection, BASF SE, Speyerer Strasse 2, 67177 Limburgerhof, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tresch
authors.affiliation: Computational Chemistry and Biology, BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wollenhaupt
authors.affiliation: Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom. Electronic address: ab454@cam.ac.uk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
mesh_terms: D016573:Agrochemicals / Q000737:chemistry*; D003198:Computer Simulation; D055808:Drug Discovery; D006540:Herbicides / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D011446:Prospective Studies; D021281:Quantitative Structure-Activity Relationship
chemical_list: D016573:Agrochemicals; D006540:Herbicides
keywords: Herbicide targets; In silico target prediction; MOLPRINT 2D; Mode of action