Fragment-based screening is now well-established as a powerful approach to early drug ("lead") discovery. Of the many suitable biophysical techniques, X-ray crystallography was one of the first to be used, and is the most directly informative (reference); however, the experimental overheads have historically been too high for it to be widely used for primary screening.
At Diamond beamline I04-1, the full X-ray screening experiment has now been implemented as a highly streamlined process, allowing up to 1000 compounds to be screened individually in less than a week (including 36 hours' unattended beamtime). The process covers soaking, harvesting, automatic data collection, and data analysis; fragment libraries are available, though users can bring their own.
Since April 2015, the XChem facility has been available to users with dedicated weekly beamtime, and is now part of the MX User Programme (apply here); as a world-wide first facility, we welcome international proposals. The future focus is on exploring how best to harness the technique to proceed rapidly to potent compounds.
Our fragment screening experiment (XChem) now routinely screens 1000 compounds in a week, so we’re not short on data. Our data shows small molecules bound to protein targets. This sort of data is commonly used in the early stages of drug discovery to begin to find bits of molecules that may eventually give us a more drug-like molecule.
Our users (and us) often have lots of hits across the protein, which is really useful information. However, we don’t yet know what the best way to use that data is to develop a drug.
Often, the computational algorithms that are applied to this challenge are only accessible to well trained computational scientists, with skills in software development and command-line interfaces as a pre-requisite. Furthermore, although there are many algorithms out there that may help to solve this problem, they’re often difficult to link together without yet more specialist expertise or experience.
Fragalysis aims to bring these tools to novice users outside of computational medicinal chemistry, providing a web-based and open source platform that will enable fast and cheap progression of fragment hits to more potent binders. We can also share our data with the wider community by curating and presenting it well on Fragalysis.