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

Autor:	Thomas SE; 1 Department of Biochemistry, University of Cambridge , Tennis Court Road, Cambridge CB2 1GA , UK., Collins P; 2 Diamond Light Source (DLS) , Harwell Science and Innovation Campus, Didcot OX11 0DE , UK., James RH; 1 Department of Biochemistry, University of Cambridge , Tennis Court Road, Cambridge CB2 1GA , UK.; 3 Sir William Dunn School of Pathology, University of Oxford , South Parks Road , Oxford OX1 3RE , UK., Mendes V; 1 Department of Biochemistry, University of Cambridge , Tennis Court Road, Cambridge CB2 1GA , UK., Charoensutthivarakul S; 4 Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW , UK., Radoux C; 5 The European Bioinformatics Institute (EMBL-EBI) , Wellcome Genome Campus, Cambridge CB10 1SD , UK., Abell C; 4 Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW , UK., Coyne AG; 4 Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW , UK., Floto RA; 6 Cambridge Centre for Lung Infection, Royal Papworth Hospital , Cambridge CB23 3RE , UK.; 7 Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-Laboratory of Molecular Biology , Cambridge CB2 0QH , UK., von Delft F; 2 Diamond Light Source (DLS) , Harwell Science and Innovation Campus, Didcot OX11 0DE , UK.; 3 Sir William Dunn School of Pathology, University of Oxford , South Parks Road , Oxford OX1 3RE , UK.; 8 Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , Oxford OX3 7DQ , UK.; 9 Department of Biochemistry, University of Johannesburg , Auckland Park 2006 , South Africa., Blundell TL; 1 Department of Biochemistry, University of Cambridge , Tennis Court Road, Cambridge CB2 1GA , UK.
Jazyk:	angličtina
Zdroj:	Philosophical transactions. Series A, Mathematical, physical, and engineering sciences [Philos Trans A Math Phys Eng Sci] 2019 Jun 17; Vol. 377 (2147), pp. 20180422.
DOI:	10.1098/rsta.2018.0422
Abstrakt:	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:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu