Fragment-based Approaches in Drug Discovery

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1 Fragment-based Approaches in Drug Discovery Edited by Wolfgang Jahnke and Daniel A. Erianson WILEY- VCH WILEY-VCH Verlag GmbH & Co. KGaA

2 Contents Preface XV A Personal Foreword List of Contributors XVII XIX Part I: Concept and Theory 1 The Concept of Fragment-based Drug Discovery 3 Daniel A. Erianson and Wolfgangjahnke 1.1 Introduction Starting Small: Key Features of Fragment-based Ligand Design FBS Samples Higher Chemical Diversity FBS Leads to Higher Hit Rates FBS Leads to Higher Ligand Efficiency Historical Development Scope and Overview of this Book 7 References 9 2 Multivalency in Ligand Design 11 Vijay M. Krishnamurthy, Lara A. Estroff, and Ceorge M. Whitesides 2.1 Introduction and Overview Definitions of Terms Selection of Key Experimental Studies Trivalency in a Structurally Simple System Cooperativity (and the Role of Enthalpy) in the "Chelate Effect" Oligovalency in the Design of Inhibitors to Toxins Bivalency at Well Defined Surfaces (Self-assembled Monolayers, SAMs) Polyvalency at Surfaces of Viruses, Bacteria, and SAMs Theoretical Considerations in Multivalency Survey of Thermodynamics Additivity and Multivalency 19 Fragment-based Approaches in Drug Discovery. Edited by W. Jahnke and D. A. Erianson Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim ISBN:

3 VI Contents Avidity and Effective Concentration (C e ff) Cooperativity is Distinct from Multivalency Conformational Entropy of the Linker between Ligands Enthalpy/Entropy Compensation Reduces the Benefit of Multivalency Representative Experimental Studies Experimental Techniques Used to Examine Multivalent Systems Isothermal Titration Calorimetry Surface Plasmon Resonance Spectroscopy Surface Assays Using Purified Components (Cell-free Assays) Cell-based Surface Assays Examination of Experimental Studies in the Context of Theory Trivalency in Structurally Simple Systems Cooperativity (and the Role of Enthalpy) in the "Chelate Effect" Oligovalency in the Design of Inhibitors of Toxins Bivalency in Solution and at Well Denned Surfaces (SAMs) Polyvalency at Surfaces (Viruses, Bacteria, and SAMs) Design Rules for Multivalent Ligands When Will Multivalency Be a Successful Strategy to Design Tight-binding Ligands? Choice of Scaffold for Multivalent Ligands Scaffolds for Oligovalent Ligands Scaffolds for Polyvalent Ligands Choice of Linker for Multivalent Ligands Rigid Linkers Represent a Simple Approach to Optimize Affinity Flexible Linkers Represent an Alternative Approach to Rigid Linkers to Optimize Affinity Strategy for the Synthesis of Multivalent Ligands Polyvalent Ligands: Polymerization of Ligand Monomers Polyvalent Ligands: Functionalization with Ligands after Polymerization Extensions of Multivalency to Lead Discovery Hetero-oligovalency Is a Broadly Applicable Concept in Ligand Design Dendrimers Present Opportunities for Multivalent Presentation of Ligands Bivalency in the Immune System A Polymers Could Be the Most Broadly Applicable Multivalent Ligands Challenges and Unsolved Problems in Multivalency Conclusions 44 Acknowledgments 45 References 45

4 Contents VII 3 Entropic Consequences of Linking Ligands 55 Christopher W. Murray and Marcel L Verdonk 3.1 Introduction Rigid Body Barrier to Binding Decomposition of Free Energy of Binding Theoretical Treatment of the Rigid Body Barrier to Binding Theoretical Treatment of Fragment Linking Experimental Examples of Fragment Linking Suitable for Analysis Estimate of Rigid Body Barrier to Binding Discussion Conclusions 64 References 65 4 Location of Binding Sites on Proteins by the Multiple Solvent Crystal Structure Method 67 Dagmar Ringe and Carlo Mattos 4.1 Introduction Solvent Mapping Characterization of Protein-Ligand Binding Sites Functional Characterization of Proteins Experimental Methods for Locating the Binding Sites of Organic Probe Molecules Structures of Elastase in Nonaqueous Solvents Organic Solvent Binding Sites Other Solvent Mapping Experiments Binding of Water Molecules to the Surface of a Protein Internal Waters Surface Waters Conservation of Water Binding Sites General Properties of Solvent and Water Molecules on the Protein Computational Methods Conclusion 85 Acknowledgments 85 References 85 Part 2: Fragment Library Design and Computional Approaches 5 Cheminformatics Approaches to Fragment-based Lead Discovery 91 Tudor I. Oprea and Jeffrey M. Blaney 5.1 Introduction The Chemical Space of Small Molecules (Under 300 a.m.u.) The Concept of Lead-likeness The Fragment-based Approach in Lead Discovery Literature-based Identification of Fragments: A Practical Example 99

5 VIII Contents 5.6 Conclusions 107 Acknowledgments 209 References Structural Fragments in Marketed Oral Drugs 113 Michal Vieth and Miles Siegel 6.1 Introduction Historical Look at the Analysis of Structural Fragments of Drugs Methodology Used in this Analysis Analysis of Similarities of Different Drug Data Sets Based on the Fragment Frequencies Conclusions 123 Acknowledgments 124 References Fragment Docking to Proteins with the Multi-copy Simultaneous Search Methodology 125 Collin M. Stultz and Martin Karplus 7.1 Introduction The MCSS Method MCSS Minimizations Choice of Functional Groups Evaluating MCSS Minima MCSS in Practice: Functionality Maps of Endothiapepsin Comparison with GRID Comparison with Experiment Ligand Design with MCSS Designing Peptide-based Ligands to Ras Designing Non-peptide Based Ligands to Cytochrome P Designing Targeted Libraries with MCSS Protein Flexibility and MCSS Conclusion 243 Acknowledgments 244 References 144 Part 3: Experimental Techniques and Applications 8 NMR-guided Fragment Assembly 249 Daniel S. Sem 8.1 Historical Developments Leading to NMR-based Fragment Assembly Theoretical Foundation for the Linking Effect NMR-based Identification of Fragments that Bind Proteins Fragment Library Design Considerations 252

6 Contents \ IX The "SHAPES" NMR Fragment Library The "SAR by NMR" Fragment Library Fragment-based Classification of protein Targets NMR-based Screening for Fragment Binding Ligand-based Methods Protein-based Methods High-throughput Screening: Traditional and TINS NMR-guided Fragment Assembly SAR by NMR SHAPES Second-site Binding Using Paramagnetic Probes NMR-based Docking Combinatorial NMR-based Fragment Assembly NMR SOLVE NMR ACE Summary and Future Prospects 176 References SAR by NMR: An Analysis of Potency Cains Realized Through Fragmentlinking and Fragment-elaboration Strategies for Lead Generation 282 PhilipJ. Hajduk, Jeffrey R. Huth, and ChaohongSun 9.1 Introduction SAR by NMR Energetic Analysis of Fragment Linking Strategies Fragment Elaboration Energetic Analysis of Fragment Elaboration Strategies Summary 290 References Pyramid: An Integrated Platform for Fragment-based Drug Discovery 193 Thomas C. Davies, Rob L M. van Montfort, Clyn Williams, and Harrenjhoti 10.1 Introduction The Pyramid Process Introduction Fragment Libraries Overview Physico-chemical Properties of Library Members Drug Fragment Library Privileged Fragment Library Targeted Libraries and Virtual Screening Quality Control of Libraries Fragment Screening X-ray Data Collection 202

7 X Contents Automation of Data Processing Hits and Diversity of Interactions Example 1: Compound 1 Binding to CDK Example 2: Compound 2 Binding to p38a Example 3: Compound 3 Binding to Thrombin Pyramid Evolution - Integration of Crystallography and NMR NMR Screening Using Water-LOGSY Complementarity of X-ray and NMR Screening Conclusions 222 Acknowledgments 211 References Fragment-based Lead Discovery and Optimization Using X-Ray Crystallography, Computational Chemistry, and High-throughput Organic Synthesis 215 JeffBlaney,Vicki Nienaber, and Stephen K. Burley 11.1 Introduction Overview of the SGX Structure-driven Fragment-based Lead Discovery Process Fragment Library Design for Crystallographic Screening Considerations for Selecting Fragments SGX Fragment Screening Library Selection Criteria SGX Fragment Screening Library Properties SGX Fragment Screening Library Diversity: Theoretical and Experimental Analyses Crystallographic Screening of the SGX Fragment Library Overview of Crystallographic Screening Obtaining the Initial Target Protein Structure Enabling Targets for Crystallographic Screening Fragment Library Screening at SGX-CAT Analysis of Fragment Screening Results Factor Vila Case Study of SGX Fragment Library Screening Complementary Biochemical Screening of the SGX Fragment Library Importance of Combining Crystallographic and Biochemical Fragment Screening Selecting Fragments Hits for Chemical Elaboration Fragment Optimization Spleen Tyrosine Kinase Case Study Fragment Optimization Overview Linear Library Optimization Combinatorial Library Optimization Discussion and Conclusions Postscript: SGX Oncology Lead Generation Program 245 References 245

8 Contents XI 12 Synergistic Use of Protein Crystallography and Solution-phase NMR Spectroscopy in Structure-based Drug Design: Strategies and Tactics 249 Cele Abad-Zapatero, Geoffrey F. Stamper, and Vincent S. Stoll 12.1 Introduction Case 1: Human Protein Tyrosine Phosphatase Designing and Synthesizing Dual-site Inhibitors The Target Initial Leads Extension of the Initial Fragment Discovery and Incorporation of the Second Fragment The Search for Potency and Selectivity Finding More "Drug-like" Molecules Decreasing Polar Surface Area on Site Monoacid Replacements on Site Core Replacement Case 2: MurF Pre-filtering by Solution-phase NMR for Rapid Co-crystal Structure Determinations The Target Triage of Initial Leads Solution-phase NMR as a Pre-filter for Co-crystallization Trials Conclusion 263 Acknowledgments 264 References Ligand SAR Using Electrospray lonization Mass Spectrometry 267 Richard H. Griffey and Eric E. Swayze 13.1 Introduction ESI-MS of Protein and RNA Targets ESI-MS Data Signal Abundances Ligands Selected Using Affinity Chromatography Antibiotics Binding Bacterial Cell Wall Peptides Kinases and GPCRs Src Homology 2 Domain Screening Other Systems Direct Observation of Ligand-Target Complexes Observation of Enzyme-Ligand Transition State Complexes Ligands Bound to Structured RNA ESI-MS for Linking Low-affinity Ligands Unique Features of ESI-MS Information for Designing Ligands 282 References 282

9 XII Contents 14 Tethering 285 Daniel A. Erianson, Marcus D. Ballinger, and James A. Wells 14.1 Introduction Energetics of Fragment Selection in Tethering Practical Considerations Finding Fragments A.I Thymidylate Synthase: Proof of Principle Protein Tyrosine Phosphatase IB: Finding Fragments in a Fragile, Narrow Site Linking Fragments Interleukin-2: Use of Tethering to Discover Small Molecules that Bind to a Protein-Protein Interface Caspase-3: Finding and Combining Fragments in One Step Caspase Beyond Traditional Fragment Discovery Caspase-3: Use of Tethering to Identify and Probe an Allosteric Site GPCRs: Use of Tethering to Localize Hits and Confirm Proposed Binding Models Related Approaches Disulfide Formation Imine Formation Metal-mediated Conclusions 308 Acknowledgments 308 References 308 Part 4: Emerging Technologies in Chemistry 15 Click Chemistry for Drug Discovery 313 Stefanie Roper and Hartmuth C. Kolb 15.1 Introduction Click Chemistry Reactions Click Chemistry in Drug Discovery Lead Discovery Libraries Natural Products Derivatives and the Search for New Antibiotics Synthesis of Neoglycoconjugates HIV Protease Inhibitors Synthesis of Fucosyltranferase Inhibitor Glycoarrays In Situ Click Chemistry Discovery of Highly Potent AChE by In Situ Click Chemistry Bioconjugation Through Click Chemistry Tagging of Live Organisms and Proteins 328

10 Contents XIII Activity-based Protein Profiling Labeling of DNA Artificial Receptors Conclusion 334 References Dynamic Combinatorial Diversity in Drug Discovery 341 Matthias Hochgiirtel and Jean-Marie Lehn 16.1 Introduction Dynamic Combinatorial Chemistry -The Principle Generation of Diversity: DCC Reactions and Building Blocks DCC Methodologies Application of DCC to Biological Systems Enzymes as Targets Receptor Proteins as Targets Nucleotides as Targets Summary and Outlook 359 References 361 Index 365

Part I: Concept and Theory

Part I: Concept and Theory Fragment-based Approaches in Drug Discovery. Edited by W. Jahnke and D. A. Erlanson Copyright # 2006 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim ISBN: 3-527-31291-9 3 1 The Concept