Targeting the Enzyme DXS using Fragment-based Design
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Herbicide resistance is a rapidly growing problem, which is beginning to seriously affect the production of food crops around the world and there is the need to identify novel targets for inhibition to overcome this. The enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS) catalyses the first and rate-limiting step of the MEP pathway and it is also involved in microbial vitamin B1 and vitamin B6 biosynthesis, making it an interesting target in microbes.
The aim will be to use fragment-based approaches to develop novel chemical tools to interrogate the role of DXS. By increasing the fundamental understanding of the nature of DXS-small molecule interactions, through X-ray crystallography, mass spectroscopy and biochemistry, this will lay the groundwork for breakthroughs in this area. This project will be carried out in collaboration with Syngenta and the student will have access to all the equipment and associated expertise and experience needed to make progress in studying DXS.
The aim will be to use fragment-based approaches to develop novel chemical tools to interrogate the role of DXS. By increasing the fundamental understanding of the nature of DXS-small molecule interactions, through X-ray crystallography, mass spectroscopy and biochemistry, this will lay the groundwork for breakthroughs in this area. This project will be carried out in collaboration with Syngenta and the student will have access to all the equipment and associated expertise and experience needed to make progress in studying DXS.
People |
ORCID iD |
| Chris Abell (Primary Supervisor) | |
| Moriam Masha (Student) |
| Description | Novel fragment binders to the protein target have been identified and validated. Biochemical evaluation of he binding mode of these fragments in comparison with known inhibitors has elucidated further information into the mechanistic action of this enzyme. Fragment binders to other enzymes within the pathway have been identified and offer unique chemical structures for further development of novel inhibitors against these herbicidal targets. |
| Exploitation Route | Structural information to support the biochemical studies is still currently underway and should help further elucidate the binding characteristics of shortlisted compounds. Synthetic elaboration of these new fragments that differ from typical inhibitors can be undertaken in order to develop novel herbicides with new modes of actions and that offer alternative routes into new chemical spaces. |
| Sectors | Agriculture, Food and Drink |