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Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

DOI: 10.1098/rsta.2018.0422 DOI Help

Authors: Sherine E. Thomas (University of Cambridge) , Patrick Collins (Diamond Light Source) , Rory Hennell James (University of Cambridge; University of Oxford) , Vitor Mendes (University of Cambridge) , Sitthivut Charoensutthivarakul (University of Cambridge) , Chris Radoux (The European Bioinformatics Institute (EMBL-EBI)) , Chris Abell (University of Cambridge) , Anthony G. Coyne (University of Cambridge) , R. Andres Floto (Royal Papworth Hospital) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , Tom Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Philosophical Transactions Of The Royal Society A: Mathematical, Physical And Engineering Sciences , VOL 377

State: Published (Approved)
Published: June 2019

Open Access Open Access

Abstract: Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources.

Journal Keywords: SAICAR synthetase (PurC); Mycobacterium abscessus; synchrotron; structure-guided; fragment-based drug discovery

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: Soleil

Added On: 01/05/2019 14:27


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening