16. The Pyramid™ Approach to Fragment-Based Biophysical Screening

  1. Matthew Cooper2 and
  2. Lorenz M. Mayr3
  1. Glyn Williams

Published Online: 24 FEB 2011

DOI: 10.1002/9780470979129.ch16

Label-Free Technologies for Drug Discovery

Label-Free Technologies for Drug Discovery

How to Cite

Williams, G. (2011) The Pyramid™ Approach to Fragment-Based Biophysical Screening, in Label-Free Technologies for Drug Discovery (eds M. Cooper and L. M. Mayr), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470979129.ch16

Editor Information

  1. 2

    Institute for Molecular Bioscience, University of Queensland, Australia

  2. 3

    Biology Unit, Protease Platform, Novartis Pharma AG, Basel, Switzerland

Author Information

  1. Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK

Publication History

  1. Published Online: 24 FEB 2011
  2. Published Print: 25 FEB 2011

ISBN Information

Print ISBN: 9780470746837

Online ISBN: 9780470979129

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Keywords:

  • The Pyramid™ Approach - to fragment-based biophysical screening;
  • screening of protein targets - using simple, low molecular weight organic compounds (‘fragments’) at high concentrations;
  • Astex and the Pyramid™ Approach - Astex Pyramid screening approach, orthogonal biophysical methods to identify fragments;
  • X-ray diffraction, method of choice - accurate structural data for protein–ligand complexes;
  • concept of ligand efficiency - or binding free energy per (nonhydrogen) atom;
  • design of fragment libraries, content of fragment screening libraries - commercial importance;
  • current Astex fragment library - and structure-based screening;
  • hits, good ligand efficiencies (LE>0.3) - affinities for target between 10mM and 100M;
  • groups at Active Sight, Astex and Vernalis - methods in screening for inhibitors of chaperone, HSP90;
  • combination of X-ray crystallography and NMR spectroscopy - good platform for fragment-based drug discovery

Summary

This chapter contains sections titled:

  • Introduction

  • Astex and the Pyramid™ Approach

  • Design of Fragment Libraries

  • Biophysical Methods in Pyramid™

  • Application of Pyramid™ to HSP90

  • Summary and Conclusions

  • Acknowledgements

  • References