Thermodynamics and Kinetics of Drug Binding

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.

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.

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 ΔG∘, ΔH∘, and ΔS∘ 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
György 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
György 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 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 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 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
György 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

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Thermodynamics and Kinetics of Drug Binding

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