Structural Biology Core

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Effective structural enablement with short turn-around and rapid dissemination of well annotated structural data provides significant impact to the hit-to-lead and lead optimization processes. This has been exemplified by the contribution of Diamond Light Source to the COVID Moonshot - an open science collaboration that developed a novel non-peptidomimetic small molecule orally bioavailable SARS-CoV-2 main viral protease (Mpro) inhibitor with potent antiviral activity starting from a high-throughput fragment screen in less than 12 months. This project has demonstrated that achieving real-time turnaround of structural data is not only technically feasible, but scientifically crucial to accelerating compound progression. Additionally, crystallographic fragment screening is a well-validated method for mapping protein ligand binding sites and identifying starting points for the development of novel therapeutics for a wide range of diseases. This technique is highly sensitive and owing to developments in synchrotron technology plus the establishment of dedicated screening facilities, such as the world-first XChem platform at Diamond Light Source, the throughput is now comparable to other biophysical techniques such as NMR and SPR with the advantage that structural information is immediately available to drive fragment-tolead development. The Structural Biology Core has been specifically situated at the Diamond Light Source's XChem facility to capitalize on its world-leading high-throughput crystallography capabilities in order to implement the logistics and technologies required to consistently achieve the acceleration required to meet the ASAP AViDD Center's ambitious medicinal chemistry goals. This core will be responsible for the successful delivery of crystallographic fragment screens, the rapid turn-around of protein-ligand crystal structures for all compounds generated by this center and ensuring all crystal structures are promptly available, at high quality and fully annotated, in the public domain.