Chapter 2. Kinases

  1. Dr. Robert E. Babine and
  2. Dr. Sherin S. Abdel-Meguid
  1. Jerry L. Adams1,
  2. James Veal2 and
  3. Lisa Shewchuk3

Published Online: 20 FEB 2004

DOI: 10.1002/3527601872.ch2

Protein Crystallography in Drug Discovery

Protein Crystallography in Drug Discovery

How to Cite

Adams, J. L., Veal, J. and Shewchuk, L. (2003) Kinases, in Protein Crystallography in Drug Discovery (eds R. E. Babine and S. S. Abdel-Meguid), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG. doi: 10.1002/3527601872.ch2

Editor Information

  1. Suntory Pharmaceutical Research Laboratories, LLC, Structural and Computational Chemistry, One Kendall Square, Bldg 700, Cambridge, MA 02139, USA

Author Information

  1. 1

    GlaxoSmithKline Pharmaceuticals Medicinal Chemistry, 1250 South Collegeville Road, Collegeville, PA 19426, USA

  2. 2

    Serenex, Inc., Informatics and Computational Chemistry, 323 Foster St., Durham, NC 27701, USA

  3. 3

    GlaxoSmithKline Pharmaceuticals Discovery Research, 5 Moore Drive, Research Triangle Park, NC 27709, USA

Publication History

  1. Published Online: 20 FEB 2004
  2. Published Print: 27 NOV 2003

Book Series:

  1. Methods and Principles in Medicinal Chemistry

Book Series Editors:

  1. Prof. Dr. Raimund Mannhold5,
  2. Prof. Dr. Hugo Kubinyi6 and
  3. Prof. Dr. Gerd Folkers7

Series Editor Information

  1. 5

    Biomedical Research Center, Molecular Drug Research Group, Heinrich-Heine-Universität, Universitätsstraße 1, 40225 Düsseldorf, Germany

  2. 6

    BASF AG Ludwigshafen, c/o Donnersbergstraße 9, 67256 Weisenheim am Sand, Germany

  3. 7

    Department of Applied Biosciences, ETH Zürich, Winterthurerstr. 190, 8057 Zürich, Switzerland

ISBN Information

Print ISBN: 9783527306787

Online ISBN: 9783527601875

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Keywords:

  • kinases;
  • structure;
  • conformation;
  • crystallization;
  • mutagenesis;
  • phosphorylation;
  • inhibitor design;
  • drug discovery;
  • selectivity

Summary

This chapter contains sections titled:

  • Introduction

  • Structure and Function

    • Tertiary Structure

    • Catalysis and Substrate Binding

    • Regulation and Conformational Flexibility

      • Activation Loop Conformation

      • Glycine Rich Loop

      • C-Helix Orientation

      • Lobe Orientation

      • Solvent Channel

  • Crystallization

    • Defining the Construct

    • Mutagenesis

    • Phosphorylation

  • Inhibitor Design

    • Binding in ATP Cleft

      • ATP Binding Sites

      • Gatekeeper-Dependent Binding Pocket

      • Lipophilic Plug

      • Polar Surface Site

    • Conformational Considerations

      • Inhibitor-Induced Binding

      • What is the Most Appropriate Enzyme Form for Crystallography?

      • Homology Models and Surrogate Kinases

    • Paradigms for Kinase Drug Discovery

      • High Throughput Screening

      • Structure-Based Design

      • Mechanism-Based and Ligand Mimetic Design

      • Computational Chemistry and Virtual Screening

    • Selectivity

  • Conclusion