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.

Herbicidal activity of isobenzofuranones and in silico identification of their enzyme target

“…The development of new herbicides can be time‐consuming and very expensive. Therefore, several researchers are using computational chemistry to speed up the process and reduce the cost of development . Among the several in silico methods available it is worth mentioning the docking and pharmacophore methods, which can be used to reveal interactions between phytotoxic compounds and their enzyme targets …”

“…Therefore, several researchers are using computational chemistry to speed up the process and reduce the cost of development. 21 Among the several in silico methods available it is worth mentioning the docking and pharmacophore methods, which can be used to reveal interactions between phytotoxic compounds and their enzyme targets. 22 Motivated by the biological activity described in the literature for natural isobenzofuranones this work was aimed at evaluating the phytotoxic activity of the , -unsaturated lactone 6, the tetrahydroisobenzofuran-1(3H)-ones (7 and 8) and the hexahydroisobenzofuran-1(3H)-ones (9-13, 14a, 14b, 15a, 15b and 16-20) in seeds of Cucumis sativus L. (cucumber), Sorghum bicolor L. Moench (sorghum), and Allium cepa L. (onion).…”

NMR as a “Gold Standard” Method in Drug Design and Discovery

“…In silico (virtual) screening is now a standard technique in drug design and discovery [ 310 ] that has been in use since at least 1991 [ 311 ], though the exact origin of the phrase “in silico” is not clear [ 312 ]. The nearly ubiquitous use of virtual screening is due to its efficiency in searching massive chemical databases in order to generate lead molecules [ 313 ] that inhibit protein-protein interactions [ 314 ], and its ability to help identity ligand (drug) binding sites on the target of interest [ 310 ] to lend insight to the mechanisms of action for lead compounds [ 315 , 316 ]. Virtual screening is often accompanied by in vitro or in vivo techniques for pharmacology drug research [ 312 ], to increase drug throughput, helping to reduce the time and cost of developing novel drug candidates [ 317 ].…”

Modern Approaches for the Development of New Herbicides Based on Natural Compounds

“…Computational methods able to predict the overall toxicity of certain molecules like PASS software [27] including herbicidal compounds [28,29] have been developed. A software for the virtual MOA identification of novel phytotoxic molecules has been created [30]. If the crystal structure of the target protein was established, the selection of optimized herbicidal molecules with maximum affinity to MT can be performed on the basis of molecular docking.…”