Fragment-Based Drug Discovery (FBDD) is a commonly used strategy for finding lead compounds as part of the drug discovery process. Since its emergence 25 years ago, it has delivered five drugs for clinical use and more than 40 molecules have been advanced to clinical trials. Fragments are small chemical entities usually with a molecular weight of 300 Da or less. They are selected for their low chemical complexity, which provide good starting points for the development of inhibitors. Their size means that they sample the binding landscape of proteins more thoroughly and provide a detailed map of the potential molecular interactions between protein and ligand.
Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive. Protein crystallography has always been a gold-standard technique, yet historically too low throughput to find widespread use as a primary screen. Initial XChem experiments were demonstrated in 2014 and then trialled with academic and industrial collaborators to validate the process. Since then, a large research effort using the crystallography labs at Research Complex at Harwell and significant beamtime at Diamond Light Source have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification.
XChem is an integral part of Diamond’s user program in collaboration with the Research Complex, with two calls per year (early April and October). The peer-review process has been refined in consultation with experts in drug discovery from Academia and Industry. Along with a strong science case, the proposal process requires applicants to self-assess not only the readiness of the crystal system, but also their expertise in biochemical and orthogonal biophysical methods and capacity to progress screening hits through follow-up chemistry.
XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 4 week turn-around for the main protease.
Douangamath, A., Powell, A., Fearon, D., Collins, P. M., Talon, R., Krojer, T., Skyner, R., Brandao-Neto, J., Dunnett, L., Dias, A., Aimon, A., Pearce, N. M., Wild, C., Gorrie-Stone, T., von Delft, F. Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source. J. Vis. Exp. (171), e62414, doi:10.3791/62414 (2021).