Full Description
There are numerous excellent reviews on fragment-based drug discovery (FBDD), but there are to date no hand-holding guides or protocols with which one can embark on this orthogonal approach to complement traditional high throughput screening methodologies. This Methods in Enzymology volume offers the tools, practical approaches, and hit-to-lead examples on how to conduct FBDD screens. The chapters in this volume cover methods that have proven to be successful in generating leads from fragments, including chapters on how to apply computational techniques, nuclear magnetic resonance, surface plasma resonance, thermal shift and binding assays, protein crystallography, and medicinal chemistry in FBDD. Also elaborated by experienced researchers in FBDD are sample preparations of fragments, proteins, and GPCR as well as examples of how to generate leads from hits.
Contents
Part I. Tools
1. Designing a Diverse High Quality Library for Crystallography Based FBDD Screening
Brett A. Tounge, Michael H. Parker
2. Preparation of Protein Samples for NMR Structure, Function, and Small-Molecule Screening Studies
Thomas B. Acton, Rong Xiao, James Aramini, William A. Buchwald, Colleen Ciccosanti, Ken Conover, Keith Hamilton, Yuanpeng Janet Huang, Haleema Janjua, Paolo Rossi, Seema Sharma, G.V.T.Swapna, Huang Wang, Li Zhao, Gaetano T. Montelione
3. Key Factors for Successful Generation of Protein-Fragment Structures: Requirements on Protein, Crystals, and Technology
Anja Jestel, Stefan Steinbacher
4. Automated Crystal Amplification and Compound Dispensation for FBDD Analysis
Francis A. Lewandowski, Brett A. Tounge, Cynthia M. Milligan
5. Hardware and Protocols for Rapid Fragment Based Structure Determination
Richard S. Alexander, John C. Spurlino
6. Using Computational Techniques in Fragment-Based Drug Discovery
Renee L. DesJarlais
7. Computational Approaches to De Novo Discovery of Fragment Binding for Unprecedented Protein States
Zenon D. Konteatis, Jinming Zou, Anthony E. Klon, Siavash Meshkat
Part II. Practical Approaches
8. How to Avoid Rediscovering the Known
Lawrence C. Kuo
9. From Experimental Design to Data Analysis: A Comprehensive Walk-Through of Fragment Identification Using Surface Plasmon Resonance
Anthony M. Giannetti
10. Practical Aspects of NMR Based Fragment Screening
Christopher Lepre
11. Fluorescent Protein Thermal Shifts to Identify Low Molecular Weight Fragments
James K. Kranz, Matthew J. Todd
12. A HTS Reporter Displacement Assay for Fragment Screening and Fragment Evolution Towards Leads with Optimized Binding Affinity, Binding Kinetics, and Kinetic Selectivity
Lars Neumann
13. Fragment Screening of Stabilized G-Protein Coupled Receptors Using Biophysical Methods
Miles Congreve, Fiona H. Marshall, David Myszka, Gregg Siegal
14. Predicting the Success of a Fragment Screening by X-Ray Crystallography
Douglas Davies, Lance Stewart
15. Fragment Screening Purely with Protein Crystallography
John C. Spurlino
16. Structure Density Relationship Based FBDD
Marta C. Abad, Xuqing Zhang, Alan C. Gibbs
Part III. Lead Generation Examples
17. Lead Generation and Examples - Opinions Regarding How to Follow Up Hits
Masaya Orita, Kazuki Ohno, Masaichi Warizaya, Yasushi Amano, Tatsuya Niimi
18. High Throughput Thermodynamics for Selection of Fragment Hits and Guidance of Fragment Evolution
Lars Neumann
19. Medicinal Chemistry Inspired Fragment Based Drug Discovery
James C. Lanter, Xuqing Zhang, Zhihua Sui
20. Experiences in Fragment-Based Lead Discovery
Roderick E. Hubbard, James B. Murray
21. Advancing Fragment Binders to Lead Like Compounds Using Ligand and Protein Based NMR Spectroscopy
Till Maurer
22. Effective Progression of NMR-Directed Fragment Hits
Hugh Eaton, Daniel Wyss
23. Fragment Screening of Infectious Disease Targets in a Structural Genomics Environment
Douglas Davies, Lance Stewart
