Antitargets and Drug Safety

List of Contributors XIII     Preface XIX     A Personal Foreword XXI     Section I: Thermodynamics 1     1 The Binding Thermodynamics of Drug Candidates 3 Ernesto Freire     1.1 Affinity Optimization 3     1.2 The Binding Affinity 4     1.3 The Enthalpy Change 6     1.4 The Entropy Change 7     1.5 Engineering Binding Contributions 9     1.6 Lipophilic Efficiency and Binding Enthalpy 11     Acknowledgments 12     References 12     2 van   t Hoff Based Thermodynamics 15 Katia Varani, Stefania Gessi, StefaniaMerighi, and Pier Andrea Borea     2.1 Relevance of Thermodynamics to Pharmacology 15     2.2 Affinity Constant Determination 16     2.3 The Origin of van   tHoff Equation 17     2.4 From van   t Hoff towardThermodynamic Discrimination 18  2.5 Representation of   G   ,   H   , and   S    Data 20     2.6 The Adenosine Receptors Binding Thermodynamics Story 21     2.7 Binding Thermodynamics of G-Protein Coupled Receptors 25     2.8 Binding Thermodynamics of Ligand-Gated Ion Channel Receptors 26     2.9 Discussion 29     Abbreviations 31     References 32     3 Computation of Drug-Binding Thermodynamics 37 Gyorgy G. Ferenczy     3.1 Introduction 37     3.2 Potential of Mean Force Calculations 39     3.3 Alchemical Transformations 41     3.4 Nonequilibrium Methods 44     3.5 MM-PBSA 44     3.6 Linear Interaction Energy 47     3.7 Scoring Functions 48     3.8 Free-energy Components 50     3.9 Summary 52     References 52     4 Thermodynamics-Guided Optimizations in Medicinal Chemistry 63 Gyorgy M. Keseru     4.1 Introduction 63     4.2 TheThermodynamics of Medicinal Chemistry Optimizations 66     4.3 Selection of Suitable Starting Points 70     4.4 Thermodynamics Based Optimization Strategies 73     References 78     5 From Molecular Understanding to Structure   Thermodynamic Relationships, the Case of Acetylcholine Binding Proteins 81 Antoni R. Blaazer and Iwan J. P. de Esch     5.1 Introduction 81     5.1.1 Natural nAChR Ligands 82     5.1.2 nAChR Ligands as Therapeutic Agents 83     5.2 Acetylcholine Binding Proteins (AChBPs) 85     5.3 Thermodynamics of Small Molecule Binding at AChBPs 89     5.4 Concluding Remarks and Outlook 98     References 99     6 Thermodynamics in Lead Optimization 107 Geoffrey A. Holdgate, Andrew Scott, and Gareth Davies     6.1 Introduction to Lead Optimization in Drug Discovery 107     6.2 Measurement ofThermodynamic Parameters in Lead Optimization 111     6.3 Advantages during Lead Optimization for Thermodynamic Measurements 117     6.4 Exploitation of Measured Thermodynamics in Lead Optimization 118     6.5 Lead Optimization beyond Affinity 120     6.6 Exemplary Case Studies 123     6.7 Potential Complicating Factors in Exploiting Thermodynamics in Lead Optimization 126     6.8 Summary 132     References 133     7 Thermodynamic Profiling of Carbonic Anhydrase Inhibitors 137 Lyn H. Jones     7.1 Introduction 137     7.2 Thermodynamic Profiles of Fragment Inhibitors 139     7.3 Thermodynamics of Fragment Growing 146     7.4 Conclusions 147     Acknowledgments 148     References 149     Section II: Kinetics 155     8 Drug   Target Residence Time 157 Robert A. Copeland     8.1 Introduction 157     8.2 Open and Closed Systems in Biology 157     8.3 Mechanisms of Drug   Target Interactions 159     8.4 Impact of Residence Time on Cellular Activity 161     8.5 Impact on Efficacy and Duration In vivo 163     8.6 Limitations of Drug   Target Residence Time 166     8.7 Summary 167     References 167     9 Experimental Methods to Determine Binding Kinetics 169 Georges Vauquelin,Walter Huber, and David C. Swinney     9.1 Introduction 169     9.2 Definitions 170     9.3 Experimental Strategy 171     9.4 Experimental Methodologies 172     9.5 Specific Issues 183     9.6 Conclusion 185     Acknowledgment 185     References 185     10 Challenges in the Medicinal Chemical Optimization of Binding Kinetics 191 Michael J.Waring, Andrew G. Leach, and Duncan C.Miller     10.1 Introduction 191     10.2 Challenges 192     10.3 Optimization in Practice 199     10.4 Summary and Conclusions 208     References 209     11 Computational Approaches for Studying Drug Binding Kinetics 211 Julia Romanowska, Daria B. Kokh, Jonathan C. Fuller, and Rebecca C.Wade     11.1 Introduction 211     11.2 Theoretical Background 211     11.3 Model Types and Force Fields 218     11.4 Application Examples 222     11.5 Summary and Future Directions 228     Acknowledgments 228     References 229     12 The Use of Structural Information to Understand Binding Kinetics 237 Felix Schiele, Pelin Ayaz, and Anke Muller-Fahrnow     12.1 Introduction 237     12.2 Binding Kinetics 238     12.3 Methods to Obtain Structural Information to Understand Binding Kinetics 241     12.4 Literature on Structure Kinetic Relationships 242     12.5 Current Thinking on the Structural Factors That Influence Binding Kinetics 251     12.6 Concluding Remarks 252     References 253     13 Importance of Drug   Target Residence Time at G Protein-Coupled Receptors     a Case for the Adenosine Receptors 257 Dong Guo, Adriaan P. IJzerman, and Laura H. Heitman     13.1 Introduction 257     13.2 The Adenosine Receptors 257     13.3 Mathematical Definitions of Drug   Target Residence Time 258     13.4 Current Kinetic Radioligand Assays 260     13.5 Dual-Point Competition Association Assay: a Fast and High-Throughput Kinetic Screening Method 261     13.6 Drug   Target Residence Time: an Often Overlooked Key Aspect for a Drug   s Mechanism of Action 267     13.7 Conclusions 270     Acknowledgments 271     References 271     14 Case Study: Angiotensin Receptor Blockers (ARBs) 273 Georges Vauquelin     14.1 Introduction 273     14.2 Insurmountable Antagonism 275     14.3 From Partial Insurmountability to an Induced Fit-Binding Mechanism 280     14.4 Sartan Rebinding Contributes to Long-Lasting AT1-Receptor Blockade 283     14.5 Summary and Final Considerations 287     References 288     15 The Kinetics and Thermodynamics of Staphylococcus aureus FabI Inhibition 295 Andrew Chang, Kanishk Kapilashrami, Eleanor K. H. Allen, and Peter J. Tonge     15.1 Introduction 295     15.2 Fatty Acid Biosynthesis as a Novel Antibacterial Target 296     15.3 Inhibition of saFabI 297     15.4 Computer-Aided Enzyme Kinetics to Characterize saFabI Inhibition 298     15.5 Orthogonal Methods to Measure Drug   Target Residence Time 298     15.6 Mechanism-Dependent Slow-Binding Kinetics 303     15.7 Mechanistic Basis for Binary Complex Selectivity 303     15.8 Rational Design of Long Residence Time Inhibition 304     15.9 Summary 306     References 307     Section III: Perspective 313     16 Thermodynamics and Binding Kinetics in Drug Discovery 315 Gyorgy M. Keseru and David C. Swinney     16.1 Introduction 315     16.2 Reaction Coordinate 316     16.3 Competing Rates 317     16.4 Thermodynamic Controlled Process     Competing Rates under Equilibrium Conditions 317     16.5 Kinetics Controlled Processes     Competing Rates under Non-equilibrium Conditions 318     16.6 Conformational Controlled Process     Kinetics as a Diagnostic for Conformational Change 319     16.7 The Value of Thermodynamics Measurements to Drug Discovery 320     16.8 Complementarity of Binding Kinetics and Thermodynamic to Discover Safer Medicines 327     References 328     Index 331