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Combining Biophysical Screening and X-Ray Crystallography for Fragment-Based Drug Discovery

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Fragment-Based Drug Discovery and X-Ray Crystallography

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 317))

Abstract

Over the past decade, fragment-based drug discovery (FBDD) has gained importance for the generation of novel ideas to inspire synthetic chemistry. In order to identify small molecules that bind to a target protein, multiple approaches have been utilized by various groups in the pharmaceutical industry and by academic groups. The combination of fragment screening by biophysical methods and in particular with surface plasmon resonance technologies (SPR) together with the visualization of the binding properties by X-ray crystallography offers a number of benefits. Screening by SPR identifies ligands for a target protein as well as provides an assessment of the binding properties with respect to affinity, stoichiometry, and specificity of the interaction. Despite the huge technology advances of the past years, X-ray crystallography is still a resource-intensive technology, and SPR binding data provides excellent measures to prioritize X-ray experiments and consequently enable a better success rate in obtaining structural information. Information on the chemical structures of fragments binding to a protein can be used to perform similarity searches in compound libraries in order to establish structure–activity relationships as well as to explore particular scaffolds. At Roche we have applied this workflow for a number of targets and the experiences will be outlined in this review.

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Abbreviations

BACE:

β-Secretase

HTS:

High-throughput screening

ITC:

Isothermal calorimetry

LIMS:

Lab information management system

NMR:

Nuclear magnetic resonance

SLS:

Swiss light source

SPR:

Surface plasmon resonance

Stdv:

Standard deviation

wt:

Wild type

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Acknowledgment

We would like to thank all colleagues at Roche involved in fragment screening and exploration work.

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Authors and Affiliations

  1. F. Hoffmann-La Roche Ltd., Pharma Research and Early Development, Discovery Technologies, Basel, 4070, Switzerland

    Michael Hennig, Armin Ruf & Walter Huber

Authors
  1. Michael Hennig
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  2. Armin Ruf
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  3. Walter Huber
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Corresponding author

Correspondence to Michael Hennig .

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Editors and Affiliations

  1. Astex Pharmaceuticals, Milton Road, Cambridge, CB4 0QA, United Kingdom

    Thomas G. Davies

  2. , Department of Biochemistry, University of Cambridge, Tennis Court Road 80, Cambridge, CB2 1GA, United Kingdom

    Marko Hyvönen

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Hennig, M., Ruf, A., Huber, W. (2011). Combining Biophysical Screening and X-Ray Crystallography for Fragment-Based Drug Discovery. In: Davies, T., Hyvönen, M. (eds) Fragment-Based Drug Discovery and X-Ray Crystallography. Topics in Current Chemistry, vol 317. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2011_225

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