Preface....................................................... XIII
List of Contributors ........................................... XV
Volume 2
Part IV. Controlling Protein-Protein Interactions
9. Diversity-oriented Synthesis .............................. 483
9.1. Diversity-oriented Synthesis ........................ 483
Derek S. Tan
Outlook ................................................... 483
9.1.1. Introduction ................................ 483
9.1.2. History/Development ......................... 484
9.1.3. General Considerations ...................... 496
9.1.4. Applications and Practical Examples ......... 502
9.1.5. Future Development .......................... 514
9.1.6. Conclusion .................................. 534
Acknowledgments ........................................... 514
References ................................................ 515
9.2. Combinatorial Biosynthesis of Polyketides and
Nonribosomal Peptides ............................... 519
Nathan A. Schnarr and Chaitan Khosla
Outlook ................................................... 519
9.2.1. Introduction ................................ 519
9.2.2. History/Development ......................... 523
9.2.3. General Considerations ...................... 527
9.2.4. Applications and Practical Examples ......... 529
9.2.5. Future Development .......................... 531
9.2.6. Conclusion .................................. 533
Acknowledgment ............................................ 534
References ................................................ 534
10. Synthesis of Large Biological Molecules ................... 537
10.1. Expressed Protein Ligation .......................... 537
Matthew R. Pratt and Tom W. Muir
Outlook ................................................... 537
10.1.1. Introduction ................................ 537
10.1.2. History/Development ......................... 538
10.1.3. General Considerations ...................... 542
10.1.4. Applications and Practical Examples ......... 548
10.1.5. Future Development .......................... 560
10.1.6. Conclusion .................................. 561
References ................................................ 561
10.2. Chemical Synthesis of Proteins and Large
Bioconjugates ....................................... 567
Philip Dawson
Outlook ................................................... 567
10.2.1. Introduction ................................ 567
10.2.2. History/Development ......................... 568
10.2.3. General Considerations ...................... 578
10.2.4. Applications and Practical Examples ......... 581
10.2.5. Future Directions ........................... 586
References ................................................ 588
10.3. New Methods for Protein Bioconjugation .............. 593
Matthew B. Francis
Outlook ................................................... 593
10.3.1. Introduction ................................ 593
10.3.2. History/Development ......................... 595
10.3.3. New Bioconjugation Methods Targeting the
Natural Amino Acids ......................... 597
10.3.4. New Methods for the Biosynthetic
Incorporation of Unnatural Functional
Groups ...................................... 612
10.3.5. New Bioconjugation Methods Targeting
Unnatural Functional Groups ................. 616
10.3.6. New Methods for Bioconjugate Purification ... 624
10.3.7. Future Development .......................... 625
10.3.8. Conclusion .................................. 628
Acknowledgments ..................................... 628
References .......................................... 629
11. Advances in Sugar Chemistry ............................... 635
11.1. The Search for Chemical Probes to Illuminate
Carbohydrate Function ............................... 635
Laura L. Kiessling and Erin E. Carlson
Outlook ................................................... 635
11.1.1. Introduction ................................ 635
11.1.2. History and Development ..................... 636
11.1.3. General Considerations: Cell-surface
Carbohydrate Recognition Interactions ....... 641
11.1.4. Applications: Identification of Inhibitors
of Protein-Carbohydrate Interactions ........ 645
11.1.5. Overview and Future Development:
Inhibition of Protein-Carbohydrate
Interactions ................................ 648
11.1.6. General Consideration: Inhibitors of
Sugar-Nucleotide-binding Enzymes ............ 648
11.1.7. Applications: Identification of Inhibitors
of Sugar-Nucleotide-binding Enzymes ......... 651
11.1.8. Overview and Future Development:
Inhibitors of Carbohydrate-processing
Enzymes ..................................... 657
11.1.9. Conclusion .................................. 658
References ................................................ 659
11.2. Chemical Glycomics as Basis for Drug Discovery ...... 668
Daniel B. Werz and Peter H. Seeberger
Outlook ................................................... 668
11.2.1. Introduction ................................ 668
11.2.2. Automated Carbohydrate Synthesis ............ 670
11.2.3. Tools for Glycomics ......................... 672
11.2.4. Oligosaccharide Conjugate Vaccines:
Malaria and HIV ............................. 677
11.2.5. Carbohydrate-Nucleic Acid Interactions:
Aminoglycosides ............................. 679
11.2.6. Carbohydrate-Protein Interactions:
Selectins and Heparin ....................... 681
11.2.7. Detection of Pathogenic Bacteria ............ 684
11.2.8. Conclusion 685 Acknowledgments .............. 687
References ................................................ 687
12. The Bicyclic Depsipeptide Family of Histone Deacetylase
Inhibitors ................................................ 693
Paul A. Townsend, Simon J. Crabb, Sean M.
Davidson, Peter W. M. Johnson, Graham Packham,
and Arasu Ganesan
Outlook ................................................... 693
12.1. Epigenetic Mechanisms of Gene Regulation ............ 694
12.2. Histone Deacetylases ................................ 696
12.3. Class I and Class II HDACs as Drug Discovery
Targets ............................................. 697
12.4. HDAC Inhibitors ..................................... 698
12.5. The Depsipeptide HDAC Inhibitors .................... 703
12.6. Total Synthesis of Depsipeptide HDAC Inhibitors -
Routes to the β-Hydroxy Acid Fragment ............... 704
12.7. Total Synthesis of Depsipeptide HDAC Inhibitors -
Peptide Synthesis and Formation of the
seco-Hydroxy Acid ................................... 706
12.8. Total Synthesis of Depsipeptide HDAC Inhibitors -
Macrocyclizations and Completion of the Synthesis ... 709
12.9. The Biological Characterization of
Spiruchostatin A .................................... 712
References ................................................ 717
Part V. Expanding the Genetic Code
13. Chemical Informatics ...................................... 723
13.1. Chemical Informatics ................................ 723
Paul A. Clemons
Outlook ................................................... 723
13.1.1. Introduction: Cheminformatics and Chemical
Space ....................................... 724
13.1.2. General Considerations: Chemical Structure
Graphs ...................................... 725
13.1.3. History and Development: Computable
Representations of Structure ................ 729
13.1.4. Applications and Examples: Molecular
Descriptor Spaces ........................... 746
13.1.5. Future Development: Multidimensional
Outcome Metrics ............................. 750
References ................................................ 753
13.2. WOMBAT and WOMBAT-PK: Bioactivity Databases for
Lead and Drug Discovery ............................. 760
Marius Olah, Ramona Rad, Liliana Ostopovici,
Alina Bora, Nicoleta Hadaruga, Dan Hadaruga,
Ramona Moldovan, Adriana Fulias, Maria Mracec,
and Tudor I. Oprea
Outlook ................................................... 760
13.2.1. Introduction: The WOMBAT Databases .......... 760
13.2.2. WOMBAT 2006.1: Overview ..................... 761
13.2.3. WOMBAT Database Structure ................... 767
13.2.4. WOMBAT Quality Control ...................... 769
13.2.5. Uncovering Errors From Literature ........... 772
13.2.6. WOMBAT-PK: Clinical Pharmacokinetics (PK)
and Toxicological (Tox) Data ................ 775
13.2.7. Datamining With WOMBAT ...................... 779
13.2.8. Conclusions and Future Challenges ........... 781
Acknowledgments ........................................... 783
References ................................................ 783
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