Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping
| Autor: | Sherine E. Thomas, Sitthivut Charoensutthivarakul, Chris J Radoux, Vitor Mendes, Frank von Delft, P.M. Collins, Chris Abell, Rory Hennell James, Tom L. Blundell, Anthony G. Coyne, R. Andres Floto |
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| Přispěvatelé: | Thomas, Sherine [0000-0003-1152-4312], Charoensutthivarakul, Sitthivut [0000-0002-4447-3438], Abell, Chris [0000-0001-9174-1987], Coyne, Anthony [0000-0003-0205-5630], Floto, Andres [0000-0002-2188-5659], Blundell, Tom [0000-0002-2708-8992], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular 0301 basic medicine General Mathematics Fragment-based lead discovery General Physics and Astronomy structure-guided Computational biology Mycobacterium abscessus History 21st Century law.invention 03 medical and health sciences 0302 clinical medicine Bacterial Proteins law synchrotron Drug Discovery Hotspot (geology) Humans Peptide Synthases Binding site Binding Sites biology Chemistry Drug discovery General Engineering Articles History 20th Century biology.organism_classification Peptide Fragments Synchrotron High-Throughput Screening Assays 030104 developmental biology 030220 oncology & carcinogenesis fragment-based drug discovery SAICAR synthetase (PurC) Synchrotrons Research Article |
| Zdroj: | Philosophical transactions. Series A, Mathematical, physical, and engineering sciences |
| ISSN: | 1471-2962 1364-503X |
| DOI: | 10.1098/rsta.2018.0422 |
| Popis: | 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 10 40 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. This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’. |
| Databáze: | OpenAIRE |
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