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NPRONET - Natural products discovery and bioengineering network

Funded Proof of Concept Projects – Call 5

Metabolomics by Automated Crystallography (MbAC): Solving the Structural Elucidation Bottleneck in Natural Product Discovery and Bioengineering through Automated Crystallisation and Single Crystal X-Ray Diffraction – Michael Hall and Michael Probert – Newcastle University

Abstract
Natural products, molecules made by bacteria, fungi, plants and animals, are a rich source of inspiration for the development of new medicines. Natural products, chemically modified natural products and synthetic molecules designed to mimic their biological effects, have been used to treat a host of diseases and conditions from pain management (e.g. aspirin and morphine) and cancer (e.g. paclitaxel and doxorubicin), to heart disease (e.g. captopril and enalapril) and infection (e.g. penicillin and tetracycline). Modern advances in the understanding and manipulation of the genes responsible for the manufacture of these natural products, by their respective producing organisms, are anticipated to revolutionise the speed at which new natural products can be discovered, even producing drug-like modified natural products directly. However a major limiting step in this discovery process is the complex and time consuming chemical analysis of the 3D structure of these new natural products. Without a clear picture of the molecular structure it is not possible to gain an understanding of the biological effects of a new natural product, let alone progress its development towards a clinical use. In this project we aim to alleviate this “bottleneck” in the discovery process through the development of a
robotic tool to increase the speed at which the molecular structure of a natural product can be solved. We aim to adapt existing robots, built to automate the crystallisation of proteins, to address the problem of natural product structure elucidation. Through new collaborations with a manufacturer of liquid handling robots and the NPRONET community, we will develop novel methods for the rapid and automated crystallisation of natural product molecules (something previously not attempted). The 3D structures of these molecules will then be unambiguously solved by single crystal X-ray analysis, through an existing collaboration between Newcastle and the Diamond Light Source (the UK’s national synchrotron science facility). A successful outcome of this project
will be the development of rapid 3D structural elucidation approaches, specifically designed for natural products, which can be easily adopted by the natural product research community. Through overcoming the existing “structural elucidation bottleneck” the discovery and understanding of new bioactive molecules will be vastly accelerated, in turn speeding up the development of new drugs to combat disease.