The XChem platform is an established, successful, high-throughput pipeline offered to Diamond users (academic and industrial) for screening of small molecules for drug discovery. XChem allows users to soak 100’s of protein crystals with different small compounds, with the diffraction data collected on the associated beamline, I04-1. Traditional protein crystal soaking methods would take months to screen a compound library, this can be achieved in a week in XChem.
There is high demand for XChem from biotech and pharmaceutical companies and they are generally very happy with their results – it is not unusual for industrial users to bring their follow up compounds back to the platform. However, they do raise points about the process that have not been addressed. One recurring concern is the potential for false negatives.
Our current protocol involves soaking a protein crystal at a high compound concentration for a defined period of time. In order to rapidly screen hundreds of compounds, we use one crystal per soaking condition for data collection. However, some crystals do not survive the compound soak, either disintegrating during the soaks or failing to diffract in the X-ray beam. So we can surmise that the fragment had a powerful effect on the crystal, but don’t know how relevant the interaction is.
Industrial users have raised concerns over these misses. Are they genuine negatives? If you used different soaking conditions would you see the same results? If you collected data from more crystals, would the same thing happen? Are we missing interesting compounds?
This project aims to address these questions. The student would gain a fully immersive experience of fragment-based crystal screening and be guided through designing and performing experiments to seek the answers. They would work primarily with the industrial XChem team, but also the academic XChem and I04-1 teams.
Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.
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