Thermodynamics and Kinetics of Drug Binding
Methods and Principles in Medicinal Chemistry 1. Aufl.
This practical reference for medicinal and pharmaceutical chemists combines the theoretical background with modern methods as well as applications from recent lead finding and optimization projects. Divided into two parts on the thermodynamics and kinetics of drug-receptor interaction, the text provides the conceptual and methodological basis for characterizing binding mechanisms for drugs and other bioactive molecules. It covers all currently used methods, from experimental approaches, such as ITC or SPR, right up to the latest computational methods. Case studies of real-life lead or drug development projects are also included so readers can apply the methods learned to their own projects. Finally, the benefits of a thorough binding mode analysis for any drug development project are summarized in an outlook chapter written by the editors.
List of Contributors XIII Preface XIX A Personal Foreword XXI Section I: Thermodynamics 1 1 The Binding Thermodynamics of Drug Candidates 3Ernesto 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 15Katia 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 182.5 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 37György 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 63György M. Keserü 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 81Antoni 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 107Geoffrey 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 137Lyn 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 157Robert 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 169Georges 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 191Michael 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 211Julia 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 237Felix Schiele, Pelin Ayaz, and Anke Müller-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 257Dong 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) 273Georges 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 295Andrew 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 315György M. Keserü 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
“Overall, the book provides a balanced view from different leaders in the field and can thus be recommended to a larger audience consisting of, but not limited to, medicinal and computational chemists, structural biologists, as well as pharmacologists and scientists, who have an interest in drug discovery and the fascinating interplay between molecular recognition and structure.” (ChemMedChem, 1 October 2015)
György Keserü obtained his Ph.D. at the University of Budapest (Hungary) and joined Sanofi-Aventis heading a chemistry research lab. In 1999, he moved to Gedeon Richter as the Head of Computer-aided Drug Discovery, being appointed as the Head of Discovery Chemistry in 2007. Since 2003, he also holds a research professorship at the Budapest University of Technology and Economics. His research interests include medicinal chemistry, drug design, and in silico ADME. He has published over 150 papers and more than 10 books and book chapters. Recently he was granted the Prous award by the European Federation of Medicinal Chemistry, EFMC.David Swinney obtained his PhD at the University of Washington in Seattle (USA). He spent 8 years at Syntex Palo Alto before moving on to Roche where he was serving as Department Head of Inflammation and Respiratory Diseases and later as Director of Biochemical Pharmacology. In 2010 he founded the Institute for Rare and Neglected Diseases, which is a non-profit drug discovery organization. Dr. Swinney is an international expert in enzymology and pharmacology with special interest in molecular mechanism of drug action and binding kinetics.
This practical reference for medicinal and pharmaceutical chemists combines the theoretical background with modern methods as well as applications from recent lead finding and optimization projects.Divided into two parts on the thermodynamics and kinetics of drug-receptor interaction, the text provides the conceptual and methodological basis for characterizing binding mechanisms for drugs and other bioactive molecules. It covers all currently used methods, from experimental approaches, such as ITC or SPR, right up to the latest computational methods. Case studies of real-life lead or drug development projects are also included so readers can apply the methods learned to their own projects. Finally, the benefits of a thorough binding mode analysis for any drug development project are summarized in an outlook chapter written by the editors.
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