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The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery

DOI: 10.1042/EBC20170051 DOI Help

Authors: Anthony R. Bradley (Structural Genomics Consortium (SGC), University of Oxford; Diamond Light Source) , Aude Echalier (Structural Genomics Consortium (SGC), University of Oxford) , Michael Fairhead (Structural Genomics Consortium (SGC), University of Oxford) , Claire Strain-damerell (Structural Genomics Consortium (SGC), University of Oxford) , Paul Brennan (Structural Genomics Consortium (SGC), University of Oxford) , Alex n. Bullock (Structural Genomics Consortium (SGC), University of Oxford) , Nicola a. Burgess-brown (Structural Genomics Consortium (SGC), University of Oxford) , Elizabeth P. Carpenter (Structural Genomics Consortium (SGC), University of Oxford) , Opher Gileadi (Structural Genomics Consortium (SGC), University of Oxford) , Brian d. Marsden (Structural Genomics Consortium (SGC), University of Oxford) , Wen hwa Lee (Structural Genomics Consortium (SGC), University of Oxford) , Wyatt Yue (Structural Genomics Consortium (SGC), University of Oxford) , Chas Bountra (Structural Genomics Consortium (SGC), University of Oxford) , Frank Von Delft (Structural Genomics Consortium (SGC), University of Oxford; Diamond Light Source; University of Johannesburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Essays In Biochemistry , VOL 61 , PAGES 495 - 503

State: Published (Approved)
Published: November 2017

Open Access Open Access

Abstract: The ongoing explosion in genomics data has long since outpaced the capacity of conventional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold-standard for early phenotypic validation towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based approaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the structural genomics initiatives of the noughties. Therefore the current, fourth funding phase of the Structural Genomics Consortium (SGC), building on its extensive experience in structural biology of novel targets and design of protein inhibitors, seeks to redefine what it means to do structural biology for drug discovery. We developed the concept of a Target Enabling Package (TEP) that provides, through reagents, assays and data, the missing link between genetic disease linkage and the development of usefully potent compounds. There are multiple prongs to the ambition: rigorously assessing targets’ genetic disease linkages through crowdsourcing to a network of collaborating experts; establishing a systematic approach to generate the protocols and data that comprise each target’s TEP; developing new, X-ray-based fragment technologies for generating high quality chemical matter quickly and cheaply; and exploiting a stringently open access model to build multidisciplinary partnerships throughout academia and industry. By learning how to scale these approaches, the SGC aims to make structures finally serve genomics, as originally intended, and demonstrate how 3D structures systematically allow new modes of druggability to be discovered for whole classes of targets.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 13/11/2017 12:00

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