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Essays Biochem. 2017 Nov 8;61(5):495-503. doi: 10.1042/EBC20170051. Print 2017 Nov 8.

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

Author information

1
Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, U.K.
2
Department of Chemistry, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.
3
Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K.
4
Department of Molecular and Cell Biology, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, U.K.
5
Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
6
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, U.K.
7
Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, U.K. frank.vondelt@sgc.ox.ac.uk.
8
Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa.

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.

KEYWORDS:

FBDD; Fragment screening; Genetic hits; SBDD; SGC; Structural Genomics

PMID:
29118096
PMCID:
PMC5869235
DOI:
10.1042/EBC20170051
[Indexed for MEDLINE]
Free PMC Article

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