Fragment to Field

A growing population, climate change and the problem of herbicide resistance is resulting in the increasing need for (better) herbicide development. With development of herbicides with novel modes of actions seemingly exhausted, the focus now is on improvement of already existing strategies. Crystallographic fragment screening is an extremely useful technique for lead generation within both the pharmaceutical and the agrochemical industries. Another useful application of fragment screening is the discovery of chemical tool compound that can be used to probe the underlying biology of the targets during biochemical and biophysical assays. The resulting increase in our understanding is both academically fascinating and translationally useful. Unfortunately, the conversion of hits to potent inhibitors remains a problematic bottleneck which leaves this method underutilised.
This project aims to develop workflows, methods and algorithms to improve efficiency of hit to herbicide conversion, enhancing the use of fragment screening and protein crystallography in herbicide discovery.
Seven approved, industrially relevant plant targets have been selected as a basis for this project. The first year will involve expression, purification and crystallisation of these targets. In subsequent years, structures of the targets will be obtained using X-ray crystallography and fragment-based screens will be conducted. The hits identified will be further tested, biophysically characterised and developed, followed by robotic synthesis and a second fragment-based screen. Next, a second round of optimisation and in vivo testing in collaboration with the industrial partner will be carried out. Based on the data obtained, workflows and algorithms will be created to facilitate progression of fragment hits to potent inhibitors and tool compounds of the targets. It may also be possible to derive strategies and rules for selection of hits (and targets).
By the end of the project, we hope to understand which strategies and rules are appropriate during herbicide design, and how they can be incorporated into workflows and algorithms for efficient fragment to field conversion.