Protein-ligand Interactions

List of Contributors XIII

Preface XVII

A Personal Foreword XIX

Part I Binding Thermodynamics 1

1 Statistical Thermodynamics of Binding and Molecular Recognition Models 3
Kim A. Sharp

1.1 Introductory Remarks 3

1.2 The Binding Constant and Free Energy 3

1.3 A Statistical Mechanical Treatment of Binding 4

1.3.1 Binding in a Square Well Potential 6

1.3.2 Binding in a Harmonic Potential 7

1.4 Strategies for Calculating Binding Free Energies 9

1.4.1 Direct Association Simulations 9

1.4.2 The Quasi-Harmonic Approximation 10

1.4.3 Estimation of Entropy Contributions to Binding 11

1.4.4 The MoleculeMechanics Poisson–Boltzmann Surface AreaMethod 13

1.4.5 Thermodynamic Work Methods 14

1.4.6 Ligand Decoupling 15

1.4.7 Linear Interaction Methods 15

1.4.8 Salt Effects on Binding 16

1.4.9 Statistical Potentials 17

1.4.10 Empirical Potentials 18

References 19

2 Some Practical Rules for the Thermodynamic Optimization of Drug Candidates 23
Ernesto Freire

2.1 Engineering Binding Contributions 25

2.2 Eliminating Unfavorable Enthalpy 25

2.3 Improving Binding Enthalpy 26

2.4 Improving Binding Affinity 27

2.5 Improving Selectivity 28

2.6 Thermodynamic Optimization Plot 28

Acknowledgments 30

References 31

3 Enthalpy–Entropy Compensation as Deduced from Measurements of Temperature Dependence 33
Athel Cornish-Bowden

3.1 Introduction 33

3.2 The Current Status of Enthalpy–Entropy Compensation 34

3.3 Measurement of the Entropy and Enthalpy of Activation 34

3.4 An Example 35

3.5 The Compensation Temperature 38

3.6 Effect of High Correlation on Estimates of Entropy and Enthalpy 39

3.7 Evolutionary Considerations 40

3.8 Textbooks 40

References 42

Part II Learning from Biophysical Experiments 45

4 Interaction Kinetic Data Generated by Surface Plasmon Resonance Biosensors and the Use of Kinetic Rate Constants in Lead Generation and Optimization 47
U. Helena Danielson

4.1 Background 47

4.2 SPR Biosensor Technology 48

4.2.1 Principles 48

4.2.2 Sensitivity 49

4.2.3 Kinetic Resolution 50

4.2.4 Performance for Drug Discovery 51

4.3 From Interaction Models to Kinetic Rate Constants and Affinity 53

4.3.1 Determination of Interaction Kinetic Rate Constants 53

4.3.2 Determination of Affinities 54

4.3.3 Steady-State Analysis versus Analysis of Complete Sensorgrams 54

4.4 Affinity versus Kinetic Rate Constants for Evaluation of Interactions 55

4.5 From Models to Mechanisms 56

4.5.1 Irreversible Interactions 57

4.5.2 Induced Fit 57

4.5.3 Conformational Selection 58

4.5.4 Unified Model for Dynamic Targets 58

4.5.5 Heterogeneous Systems/Parallel Reactions 59

4.5.6 Mechanism-Based Inhibitors 60

4.5.7 Multiple Binding Sites and Influence of Cofactors 61

4.6 Structural Information 61

4.7 The Use of Kinetic Rate Constants in Lead Generation and Optimization 62

4.7.1 Structure–Kinetic Relationships 62

4.7.2 Selectivity/Specificity and Resistance 63

4.7.3 Chemodynamics 63

4.7.4 Thermodynamics 64

4.8 Designing Compounds with Optimal Properties 65

4.8.1 Correlation between Kinetic and Thermodynamic Parameters and Pharmacological Efficacy 65

4.8.2 Structural Modeling 66

4.9 Conclusions 67

Acknowledgments 67

References 67

5 NMR Methods for the Determination of Protein–Ligand Interactions 71
Bernd W. Koenig, Sven Schünke, Matthias Stoldt, and Dieter Willbold

5.1 Experimental Parameters from NMR 72

5.2 Aspects of Protein–Ligand Interactions That Can Be Addressed by NMR 77

5.2.1 Detection and Verification of Ligand Binding 77

5.2.2 Interaction Site Mapping 78

5.2.3 Interaction Models and Binding Affinity 80

5.2.4 Molecular Recognition 81

5.2.5 Structure of Protein–Ligand Complexes 82

5.3 Ligand-Induced Conformational Changes of a Cyclic Nucleotide Binding Domain 84

5.4 Ligand Binding to GABARAP Binding Site and Affinity Mapping 86

5.5 Transient Binding of Peptide Ligands to Membrane Proteins 88

References 90

Part III Modeling Protein–Ligand Interactions 99

6 Polarizable Force Fields for Scoring Protein–Ligand Interactions 101
Jiajing Zhang, Yue Shi, and Pengyu Ren

6.1 Introduction and Overview 101

6.2 AMOEBA Polarizable Potential Energy Model 102

6.2.1 Bond, Angle, and Cross-Energy Terms 102

6.2.2 Torsional Energy Term 103

6.2.3 Van der Waals Interactions 103

6.2.4 Permanent Electrostatic Interactions 103

6.2.5 Electronic Polarization 104

6.2.6 Polarization Energy 105

6.3 AMOEBA Explicit Water Simulation Applications 106

6.3.1 Small-Molecule Hydration Free Energy Calculations 106

6.3.2 Ion Solvation Thermodynamics 108

6.3.3 Binding Free Energy of Trypsin and Benzamidine Analogs 110

6.4 Implicit Solvent Calculation Using AMOEBA Polarizable Force Field 113

6.5 Conclusions and Future Directions 115

References 116

7 Quantum Mechanics in Structure-Based Ligand Design 121
Pär Söderhjelm, Samuel Genheden, and Ulf Ryde

7.1 Introduction 121

7.2 Three MM-Based Methods 122

7.3 QM-Based Force Fields 123

7.4 QM Calculations of Ligand Binding Sites 125

7.5 QM/MM Calculations 126

7.6 QM Calculations of Entire Proteins 127

7.6.1 Linear Scaling Methods 128

7.6.2 Fragmentation Methods 129

7.7 Concluding Remarks 133

Acknowledgments 134

References 134

8 Hydrophobic Association and Volume-Confined Water Molecules 145
Riccardo Baron, Piotr Setny, and J. Andrew McCammon

8.1 Introduction 145

8.2 Water as a Whole in Hydrophobic Association 146

8.2.1 Background 146

8.2.2 Computational Modeling of Hydrophobic Association 150

8.2.2.1 Explicit versus Implicit Solvent: Is the Computational Cost Motivated? 152

8.3 Confined Water Molecules in Protein–Ligand Binding 153

8.3.1 Protein Hydration Sites 153

8.3.2 Thermodynamics of Volume-Confined Water Localization 154

8.3.3 Computational Modeling of Volume-Confined Water Molecules 156

8.3.4 Identifying Hydration Sites 158

8.3.5 Water in Protein–Ligand Docking 160

Acknowledgments 161

References 161

9 Implicit Solvent Models and Electrostatics in Molecular Recognition 171
Tyler Luchko and David A. Case

9.1 Introduction 171

9.2 Poisson–Boltzmann Methods 173

9.3 The Generalized Born Model 175

9.4 Reference Interaction Site Model of Molecular Solvation 176

9.5 Applications 179

9.5.1 The ‘‘MM-PBSA’’ Model 180

9.5.2 Rescoring Docking Poses 182

9.5.3 MM/3D-RISM 182

Acknowledgments 185

References 185

10 Ligand and Receptor Conformational Energies 191
Themis Lazaridis

10.1 The Treatment of Ligand and Receptor Conformational Energy in Various Theoretical Formulations of Binding 191

10.1.1 Double Decoupling Free Energy Calculations 192

10.1.2 MM-PB(GB)SA 192

10.1.3 Mining Minima 193

10.1.4 Free Energy Functional Approach 194

10.1.5 Linear Interaction Energy Methods 195

10.1.6 Scoring Functions 196

10.2 Computational Results on Ligand Conformational Energy 196

10.3 Computational Results on Receptor Conformational Energy 198

10.4 Concluding Remarks 199

Acknowledgments 199

References 199

11 Free Energy Calculations in Drug Lead Optimization 207
Thomas Steinbrecher

11.1 Modern Drug Design 207

11.1.1 In Silico Drug Design 210

11.2 Free Energy Calculations 212

11.2.1 Considerations for Accurate and Precise Results 215

11.3 Example Protocols and Applications 217

11.3.1 Example 1: Disappearing an Ion 219

11.3.2 Example 2: Relative Ligand Binding Strengths 221

11.3.3 Applications 223

11.4 Discussion 226

References 227

12 Scoring Functions for Protein–Ligand Interactions 237
Christoph Sotriffer

12.1 Introduction 237

12.2 Scoring Protein–Ligand Interactions: What for and How to? 237

12.2.1 Knowledge-Based Scoring Functions 238

12.2.2 Force Field-Based Methods 240

12.2.3 Empirical Scoring Functions 242

12.2.4 Further Approaches 244

12.3 Application of Scoring Functions: What Is Possible and What Is Not? 246

12.4 Thermodynamic Contributions and Intermolecular Interactions: Which Are Accounted for and Which Are Not? 248

12.5 Conclusions or What Remains to be Done and What Can be Expected? 254

Acknowledgments 255

References 255

Part IV Challenges in Molecular Recognition 265

13 Druggability Prediction 267
Daniel Alvarez-Garcia, Jesus Seco, Peter Schmidtke, and Xavier Barril

13.1 Introduction 267

13.2 Druggability: Ligand Properties 267

13.3 Druggability: Ligand Binding 268

13.4 Druggability Prediction by Protein Class 270

13.5 Druggability Predictions: Experimental Methods 270

13.5.1 High-Throughput Screening 270

13.5.2 Fragment Screening 271

13.5.3 Multiple Solvent Crystallographic Screening 272

13.6 Druggability Predictions: Computational Methods 272

13.6.1 Cavity Detection Algorithms 272

13.6.2 Empirical Models 273

13.6.2.1 Training Sets 273

13.6.2.2 Applicability and Prediction Performance 274

13.6.3 Physical Chemistry Predictions 275

13.7 A Test Case: PTP1B 276

13.8 Outlook and Concluding Remarks 278

References 278

14 Embracing Protein Plasticity in Ligand Docking 283
Manuel Rueda and Ruben Abagyan

14.1 Introduction 283

14.2 Docking by Sampling Internal Coordinates 284

14.3 Fast Docking to Multiple Receptor Conformations 285

14.4 Single Receptor Conformation 285

14.5 Multiple Receptor Conformations 286

14.5.1 Exploiting Existing Experimental Conformational Diversity 286

14.5.2 Selecting ‘‘Important’’ Conformations 288

14.5.3 Generating In Silico Models 288

14.6 Improving Poor Homology Models of the Binding Pocket 289

14.7 State of the Art: GPCR Dock 2010 Modeling and Docking Assessment 290

14.8 Conclusions and Outlook 290

Acknowledgments 292

References 292

15 Prospects of Modulating Protein–Protein Interactions 295
Shijun Zhong, Taiji Oashi, Wenbo Yu, Paul Shapiro, and Alexander D. MacKerell Jr.

15.1 Introduction 295

15.2 Thermodynamics of Protein–Protein Interactions 297

15.3 CADD Methods for the Identification and Optimization of Small-Molecule Inhibitors of PPIs 298

15.3.1 Identifying Inhibitors of PPIs Using SBDD 299

15.3.1.1 Protein Structure Preparation 299

15.3.1.2 Binding Site Identification 300

15.3.1.3 Virtual Chemical Database 302

15.3.1.4 Virtual Screening of Compound Database 302

15.3.1.5 Rescoring 304

15.3.1.6 Final Selection of Ligands for Experimental Assay 306

15.3.2 Lead Optimization 307

15.3.2.1 Ligand-Based Optimization 307

15.3.2.2 Computation of Binding Free Energy 308

15.4 Examples of CADD Applied to PPIs 308

15.4.1 ERK 309

15.4.2 BCL6 311

15.4.3 S100B 313

15.4.4 p56Lck Kinase SH2 Domain 313

15.5 Summary 315

Acknowledgments 315

References 315

Index 331

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