21004SP Multi-Step robotic synthesis to speed up early-stage drug discovery

XChem is a fragment screening facility that uses the X-rays to identify fragments binding to proteins of high biological relevance (cancer treatment, bacteria resistance...). Every day, 500 fragments can be analysed per protein, and new fragments hits are discovered. However, there is no systematic approach for the progression of these weak fragments to drug-like compounds.

The XChem group has sought to address the downstream bottleneck with a liquid handling robot for automated high-throughput synthetic chemistry. Costs and time savings compared to conventional bench chemistry would allow the testing of 100s of compounds when only a handful are currently investigated. We believe that it is necessary to get a better understanding of ligand-protein interactions for a rapid design and production of more potent compounds.

In this summer project, the student will use a photo-chemical reaction within a four-step sequence to synthesise 100s of follow-up compounds derived from a fragment hit obtained during the screen of a protein. The focus will be on establishing a protocol for automating several reactions with the liquid handler that will reliably yield products in 30-40mg quantities. These follow-up compounds will then be screened by X-ray, providing crucial data on the binding mode of the ligands. 

In the event of stringent lab restrictions next summer, the project will refocus on the remote multi-step coding of the robot and less experimental synthesis in the lab.