Volume 3
Part VI. Forward Chemical Genetics
14. Chemical Biology and Drug Discovery ....................... 789
14.1. Managerial Challenges in Implementing Chemical
Biology Platforms ................................... 789
Frank L. Douglas
14.1.1. Introduction ................................ 789
14.1.2. The Management Challenge .................... 789
14.1.3. Observation-based Discovery Background ...... 791
14.1.4. Mechanism-based Discovery Background ........ 793
14.1.5. Twenty-first Century Experience: Ketek
(Novel Anti-infective Drug in 2003) ......... 794
14.1.6. Observation Summary and Future
Application ................................. 795
14.1.7. Establishment of Organizational Structures
for Chemical Biology Platforms .............. 796
14.1.8. Chemical Biology Platforms (СВР) ............ 798
14.1.9. Other Organizational and Knowledge
Challenges .................................. 801
14.1.10.Conclusion .................................. 802
References ................................................ 803
14.2. The Molecular Basis of Predicting Draggability ...... 804
Bissan Al-Lazikani, Anna Gaulton, Gaia Paolini,
Jerry Lanfear, John Overington, and Andrew Hopkins
14.2.1. Introduction ................................ 804
14.2.2. Chemical Properties of Drugs, Leads,
and Tools ................................... 805
14.2.3. Molecular Recognition is the Basis for
Draggability ................................ 805
14.2.4. Estimating the Size of the Druggable
Genome ...................................... 808
14.2.5. How Many Drug Targets are Accessible to
Protein Therapeutics ........................ 817
14.2.6. Conclusion .................................. 819
Acknowledgments ........................................... 822
References ................................................ 822
15. Target Families ........................................... 825
15.1. The Target Family Approach .......................... 825
Hans Peter Nestler
Outlook ................................................... 825
15.1.1. Introduction ................................ 825
15.1.2. Understanding Biological Space .............. 828
15.1.3. Exploring Chemical Space .................... 834
15.1.4. Epilogue .................................... 846
References ................................................ 847
15.2. Chemical Biology of Kinases Studied by NMR
Spectroscopy ........................................ 852
Marco Betz, Martin Vogtherr, Ulrich Schieborr,
Bettina Elshorst, Susanne Grimme, Barbara
Pescatore, Thomas Langer, Krishna Saxena,
and Harold Schwalbe
Outlook ................................................... 852
15.2.1. Introduction ................................ 852
15.2.2. Protein NMR Spectroscopy on Kinases ......... 856
15.2.3. Screening of Kinases by NMR ................. 875
15.2.4. Characterizing Kinase-Ligand Interactions
by NMR ...................................... 882
References ................................................ 887
15.3. The Nuclear Receptor Superfamily and Drug
Discovery ........................................... 891
John T. Moore, Jon L. Collins, and Kenneth H.
Pearce
Outlook ................................................... 891
15.3.1. Introduction ................................ 891
15.3.2. Brief History of NRs in Medicine and Drug
Discovery ................................... 901
15.3.3. Basic Principles for Ligand-NR
Recognition ................................. 903
15.3.4. Influence of Ligand on NR LBD
Conformation ................................ 909
15.3.5. The Multitude of Ligand-induced NR
Actions ..................................... 913
15.3.6. Specific Examples of Recent NR Drugs and
Novel Drug Candidates ....................... 916
15.3.7. New Approaches to NR Drug Discovery ......... 920
15.3.8. Future Developments and Conclusions for NR
Chemical Biology ............................ 923
Acknowledgment ............................................ 924
References ................................................ 924
15.4. The GPCR - 7TM Receptor Target Family ............... 933
Edgar Jacoby, Rochdi Bouhelal, Marc Gerspacher,
and Klaus Seuwen
Outlook ................................................... 933
15.4.1. Introduction ................................ 933
15.4.2. History/Development ......................... 938
15.4.3. General Considerations ...................... 943
15.4.4. Applications and Practical Examples ......... 960
15.4.5. Future Development .......................... 968
15.4.6. Conclusions ................................. 970
Acknowledgments ........................................... 971
References ................................................ 971
15.5. Drugs Targeting Protein-Protein Interactions ........ 979
Patrick Ch&@232;ne
Outlook ................................................... 979
15.5.1. Introduction ................................ 979
15.5.2. The Diversity of Protein-Protein
Interfaces .................................. 980
15.5.3. A Proposed Decision Tree to Select
Interfaces for Drug Discovery ............... 984
15.5.4. Experimental Validation of the Selected
Interface ................................... 988
15.5.5. Screening Techniques, Compound Libraries,
and Targets ................................. 989
15.5.6. An Example: The Design of Inhibitors of
the p53-hdm2 Interaction .................... 991
15.5.7. Conclusions ................................. 998
References ................................................ 999
16. Prediction of ADM ET Properties .......................... 1003
Ulf Norinder and Christel A. S. Bergström
Outlook .................................................. 1003
16.1. Introduction ....................................... 2003
16.1.1. Drug Solubility ............................ 1007
16.1.2. Intestinal Permeability .................... 1007
16.1.3. Toxicity ................................... 1008
16.2. History and Development ............................ 1008
16.3. General Considerations ............................. 1009
16.3.1. General Terms .............................. 1009
16.3.2. Datasets and Models ........................ 1010
16.3.3. Statistical Tools .......................... 1011
16.4. Applications and Practical Examples ................ 1018
16.4.1. Physiological Factors and Experimental
Parameters Influencing the Accuracy of
Predictions of Intestinal Drug
Absorption ................................. 1038
16.4.2. In silico Solubility Models ................ 1022
16.4.3. In stfico Models of Permeability and FA .... 3026
16.4.4. A Computer-based Biopharmaceutical
Classification System ...................... 1032
16.4.5. In silico Toxicity Models .................. 1033
16.5. Future Development and Conclusions ................. 1035
Acknowledgments .......................................... 1036
References ............................................... 1038
Part VII. Reverse Chemical Genetics Revisited
17. Computational Methods and Modeling ....................... 1045
17.1. Systems Biology of the JAK-STAT Signaling
Pathway ............................................ 1045
Jens Timmer, Markus Kallmann,
and Ursula Klingmüller
Outlook .................................................. 1045
17.1.1. Introduction ............................... 1045
17.1.2. History Development ........................ 1046
17.1.3. General Considerations ..................... 1047
17.1.4. Practical Example .......................... 1049
17.1.5. Future Development ......................... 1057
References ............................................... 1058
17.2. Modeling Intracellular Signal Transduction
Processes .......................................... 1061
Jason M. Haugh and Michael C. Weiger
Outlook .................................................. 1063
17.2.1. Introduction ............................... 3063
17.2.2. Receptor-Binding and Regulation
Mechanisms ................................. 1062
17.2.3. Receptor-mediated Covalent Modifications
and Molecular Interactions ................. 1065
17.2.4. Spatial Organization and Gradients on
Cellular and Subcellular Length Scales ..... 1069
17.2.5. Downstream Signaling Cascades and
Networks ................................... 1072
17.2.6. Prospects and Challenges ................... 1074
17.2.7. Concluding Remarks ......................... 1077
Acknowledgments .......................................... 1077
References ............................................... 1077
18. Genome and Proteome Studies .............................. 1083
18.1. Genome-wide Gene Expression Analysis: Practical
Considerations and Application to the Analysis
of T-cell Subsets in Inflammatory Diseases ......... 1083
Lars Rogge and Elisabetta Bianchi
Outlook .................................................. 1083
18.1.1. Introduction ............................... 1083
18.1.2. History/Development ........................ 1084
18.1.3. General Considerations ..................... 1085
18.1.4. Applications and Practical Examples ........ 1097
18.1.5. Future Development ......................... 1109
References ............................................... 1110
18.2. Scanning the Proteome for Targets of Organic
Small Molecules Using Bifunctional Receptor
Ligands ............................................ 1118
Nikolai Kley
Outlook .................................................. 1118
18.2.1. Introduction ............................... 1118
18.2.2. History and Development .................... 1120
18.2.3. General Considerations ..................... 1127
18.2.4. Applications and Practical Examples ........ 1129
18.2.5. Future Developments ........................ 1132
18.2.6. Conclusions ................................ 1135
Acknowledgments .......................................... 1135
References ............................................... 1135
Part VIII Tags and Probes for Chemical Biology
19. Chemical Biology - An Outlook ............................ 1143
Günther Wess
Outlook .................................................. 1143
19.1. The Evolving Concept of Chemical Biology ........... 1143
19.2. Chemical Biology in Academia ....................... 1144
19.3. Chemical Biology in Industry ....................... 1146
19.4. Chemical Biology and Translational Medicine ........ 1148
19.5. Knowledge and Networks, Education and Training ..... 1148
19.6. Conclusion ......................................... 1149
Acknowledgment ........................................... 1150
References ............................................... 1150
Index ........................................................ 1151
|
