Lipophilicity in DrugAction and Toxicology

edited byVladimir PliskaBernard TestaHan van de Waterbeemd

VCH Weinheim • New York • Basel • Cambridge • Tokyo

Contents

Preface V

A Personal Foreword VII

List of Contributors IX

1 Lipophilicity: The Empirical Tool and the Fundamental Objective.An Introduction 1V. Pliska, B. Testa and H. Van de Waterbeemd

1.1 Setting the Scene 11.2 Biological Aspects 11.3 The Molecule in the Background 21.4 Some Pragmatic Aspects 31.4.1 Definitions and Symbols 31.4.2 Experimental Techniques 41.4.3 Computational Procedures 51.5 Objectives of the Book 5

References 6

2 Lipophilicity: A History 7M. S. Tute

2.1 Introduction 72.2 Measurement of Lipophilicity 92.3 Calculation of Lipophilicity 112.3.1 Substitution Method 112.3.2 Fragment Additivity Method 122.3.3 Fragmentation into Atoms 132.3.4 Molecular Orbital Calculations 142.3.5 Calculations Based on Surface Area 142.4 The Nature of Lipophilicity 172.4.1 Relation to Other Molecular Properties 182.4.2 Thermodynamics of Partitioning . 192.4.2.1 Phase Transfer 192.4.2.2 The Aqueous Phase and the "Hydrophobic Bond" 212.5 Lipophilicity and Biological Activity 22

References 24

XIV Contents

3 Thermodynamics of van der Waals and HydrophobicInteractions 27R. Zahradnik and P. Hobza

3.1 Introduction 283.2 Outline of Thermodynamics and Auxiliary Disciplines 313.3 Intermolecular Interactions of the van der Waals Type 333.3.1 The Physical Nature of van der Waals Interactions 333.3.2 Classification of van der Waals Clusters 343.3.3 Calculation of the Interaction Energy 343.3.3.1 Nonempirical ab initio Variational Method 353.3.3.2 Density Functional Theory 363.3.3.3 Semiempirical Methods 363.3.3.4 Empirical Procedures 363.3.4 How to Obtain a Consistent Set of Various Calculated Properties

for van der Waals Clusters 373.3.4.1 Potential Energy Surface (P. E. S.) 373.3.4.2 Stabilization Energy 373.3.4.3 Empirical Potential 383.3.4.4 Vibration Frequencies 383.3.4.5 Computer Experiments 383.4 Processes Involving Hydrophobic Effects 383.5 Specific Illustrations 403.5.1 Ab initio Evaluation of a Consistent Set of Various

Properties of the Benzene . . . Arn Cluster 403.5.1.1 Potential Energy Surface 403.5.1.2 More Accurate Calculations for the Global Minimum 413.5.1.3 Preparation of the Empirical Potential 413.5.1.4 Vibrational Frequencies 423.5.1.5 Molecular Dynamics Simulations 423.5.2 Monte Carlo Free Energy Perturbation Calculation: Solvation Free

Energy of Methanol and Ethane 43References 43Appendices 45

4 Intramolecular Interactions Encoded in Lipophilicity:Their Nature and Significance 49B. Testa, P.-A. Carrupt, P. Gaillard and R.-S. Tsai

4.1. Introduction: The Concept of Molecular Structure 494.1.1 The Elementary and Geometric Levels of Description 494.1.2 The Stereoelectronic Levels of Description 504.1.3 Social Molecules 514.2 Intermolecular Forces Encoded in Lipophilicity 524.2.1 Recognition Forces in Molecular Pharmacology and Biology 524.2.2 Factorization of Molecular Lipophilicity 53

Contents XV

4.2.3 Polar Interactions Encoded in Lipophilicity 544.2.4 Nonpolar Interactions Encoded in Lipophilicity 554.2.5 Recognition Forces Encoded in Lipophilicity 554.3 Intramolecular Interactions Affecting Lipophilicity 554.3.1 Electronic Conjugations 564.3.1.1 In Aromatic Systems 564.3.1.2 Across Aliphatic Segments 574.3.2 Interactions Involving Polar Groups 584.3.2.1 Proximity Effects Between Two Neutral Polar Groups 584.3.2.2 Internal H-bonds 594.3.2.3 The Case of Zwitterions 614.3.2.4 Hydrophilic Collapse 624.3.2.5 Proximity Effects Between Polar and Nonpolar Groups 634.3.3 Steric/Hydrophobic Effects 644.3.3.1 Shielding of Polar Groups 644.3.3.3 Hydrophobic Collapse 654.4 Structural Factors Influencing Intramolecular Interactions 654.4.1 Positional Isomerism 664.4.2 Stereoisomerism 674.4.3 Ionization 674.4.4 Molecular Size and Chameleonic Behavior 684.5 Outlook: Molecular Polymorphism in Drug Design 69

Acknowledgements 70References 70

5 Lipophilicity Measurement by Reversed-PhaseHigh Performance Liquid Chromatography (RP-HPLC) . . . . 73H. van de Waterbeemd, M. Kansy, B. Wagner and H. Fischer

5.1 Historical 745.2 Principle of Lipophilicity Measurements by RPLC 745.2.1 Description of the Method 745.2.2 Log k or log kw 765.3 Stationary Phases (Column Packings) 775.3.1 Overview 775.3.2 New HPLC Packing Materials for Lipophilicity Measurements . . . . 785.3.3 Column Length 785.4 Mobiles Phases 785.4.1 Selection of Organic Modifier 785.4.2 Buffer and the Effect of Ionization . 795.4.2.1 Buffer 795.4.2.2 Ionization Correction 795.4.3 Masking Agents " 7 95.4.4 Ion Pairs and Ion Pair Chromatography (IPC) 80

XVI Contents

5.5 Retention Mechanism 805.5.1 Solvatochromic Analysis 805.5.2 Slope Analysis and Hydrogen-Bonding Capacity 815.5.3 Effect of Intercharge Distance in Zwitterions 825.5.4 Effect of Conformation on Retention 825.5.5 Lipophilicity of Peptides and Proteins 835.6 Correlations of log &w Values to log Poct and Other log P Scales . . . . 835.7 Recommendations 855.7.1 OECD/EU Guidelines 855.7.2 Recommended Method 85

Acknowledgements 85References 85

6 Centrifugal Partition Chromatography for LipophilicityMeasurements 89R.-S. Tsai, G. Lisa, P.-A. Corrupt and B. Testa

6.1 Introduction: a Need for an Accurate Method for PartitionCoefficient Measurements 89

6.2 Historical Aspects 916.2.1 The Discovery and Development of CPC 916.2.2 From log POctanoi-hexane/water to log Poa Using Multichannel

Cartridge-type CPC 926.2.3 From log Foct to log P (Solvent "quartet") Using Coil

Planet-type CPC 926.3 Mechanisms of Solute Partitioning in Various Types of CPC 936.3.1 Hydrostatic Equilibrium Systems 936.3.2 Hydrodynamic Equilibrium Systems 956.4 Method Development for log P Measurements Using CPC 966.4.1 Calculation of Partition Coefficients 966.4.2 Considerations About the Equipment (Mainly the Centrifuge) . . . . 966.4.3 Experimental Design 986.5 Validation of log P Values Obtained from CPC 1006.5.1 Partition Coefficients in rc-Octanol/Water Systems 1016.5.2 Partition Coefficients in Alkane/Water Systems 1016.5.3 Partition Coefficients in di-n-Butyl Ether/Water and Chloroform/

Water Systems 1026.6 Application to the Determination of Solute Structural Properties . . . 1026.6.1 The Case of Zwitterionic Amino Acids 1026.6.2 The Case of Anti-Dopaminergic 6-Methoxysalicylamides 1046.7 Advantages and Limitations of the CPC Method for log P

Measurements 1046.8 Concluding Remarks 105

Acknowledgments 106References 106

Contents XVII

7 Assessment of Distribution-pH Profiles 109A. Avdeef

7.1 Introduction 1097.2 Partition Coefficient, log P, and the Dyrssen Two-Phase Titration . . 1107.2.1 Historical Background 1107.2.2 Titrations 1107.2.3 Bjerrum Difference Plots 1127.2.4 pH Definitions and Electrode Standardization 1137.2.5 Definitions of Constants 1147.3 Distribution Function (D) and the Lipophilicity Profile

( logDvspH) 1157.3.1 Experimental Evidence for Ion-Pairing: Shake-Flask

vs pH-Metric 1187.3.2 Further Insights into the Scherrer p# a 1217.3.3 pH Scale in Lipids? 1227.3.4 Monoprotic Substance log D-pH Curve Shape Analysis 1237.3.5 Application of Shape Analysis to One-Point log D Shake-Flask

Measurement 1237.3.6 Effect of Salt: Monoprotic Examples 1267.3.7 Debye-Hiickel Corrections to Octanol/Water Partition Constants . . 1277.3.8 Diprotic Substance log D-pH Curve Shape Analysis (12 Cases) . . . 1287.3.9 Diprotic Molecules with Two Different Ion Pair Partitionings . . . . 1297.3.10 Macm-pKa, Micro-p^, and Zwitterions 1317.3.11 Relationship between Micro-log P, Macro-log p, and log D 1327.3.12 Micro-logp Application 1337.3.13 Partitioning of the Amino Acids Phenylalanine and

Tryptophanylphenylalanine 1337.3.14 Partitioning of Morphine Derivatives and Metabolites 1357.3.15 Drug-Liposome Partitioning, First Look 1367.4 Outlook 136

Acknowledgements 137References • 137

8 Estimation of Lipophilicity by Reversed-Phase Thin-LayerChromatography 141R. Mannhold, K. Dross and C. Sonntag

8.1 Introduction 1418.2 Stationary Phase 1438.3 Mobile Phase 1458.3.1 The Influence of the Organic Modifier on RM 1458.3.2 The Influence of Solvent pH and Ionic Strength on RM 1458.4 RMvi and Extrapolation Methods 1468.4.1 Quadratic Function 1478.4.2 Exponential Function 147

XVIII Contents

8.4.3 Mixed Exponential/Linear Function 1488.5 Analysis of the RM/cp Relation 1488.6 Comparison with Other Lipophilicity Data 1498.6.1 The Comparison of RMvl with log kw 1498.6.2 The Comparison of RMw with log POct 1498.6.3 The Comparison of RMw with Calculated log P 1528.7 Concluding Remarks 153

References 154

9 The Future of log P Calculation 157A.J. Leo

9.1 Introduction 1579.2 Methods 1589.2.1 The Substituent Method 1589.2.2 Atom-Based Methods 1589.2.3 Methods Based on Molecular Properties 1599.2.4 Fragment-Based Methods 1619.3 Common Problems 1619.3.1 How is the "True" Structure to be Represented? 1619.3.2 Intramolecular H-bonding 1659.4 Conclusions 170

References 171

10 Theoretical Calculation of Partition Coefficients 173W. G. Richards

10.1 Introduction 17310.2 Statistical Thermodynamics 17410.3 Equilibrium Constants 17410.4 Free Energy Perturbation Calculations 17510.5 Partition Coefficients 17610.6 Membrane Simulations 17810.7 Future Outlook 180

References 180

11 Cellular Automata Model of Partitioning BetweenLiquid Phases 181L. B. Kier and C.-K. Cheng

11.1 Introduction 18111.2 Cellular Automata 18211.2.1 The Model 18211.2.2 The Molecular System 18311.2.3 The Dimensional Relationship in Cellular Automata Models . . . . 18411.2.4 The Rules 184

Contents XIX

11.3 Models of Solution Phenomena 18511.3.1 A Model of Water 18511.3.2 A Model of a Solution 18611.3.3 A Model of the Hydrophobic Effect 18611.3.4 A Model of Dissolution 18611.4 A Cellular Automata Model of Immiscibility 18711.4.1 Immiscible Liquids 18711.4.2 A Model of Immiscible Systems 18711.4.3 An Immiscible Liquid Simulation 18811.5 A Model of Partitioning Between Immiscible Liquids 19011.6 Conclusion 192

Acknowledgements 193References 194

12 The Molecular Lipophilicity Potential (MLP): A New Toolfor log P Calculations and Docking and in ComparativeMolecular Field Analysis (CoMEA) 195P.-A. Carrupt, P. Gaillard, F.Billois, P. Weber, B. Testa,C. Meyer and S. Perez

12.1 Computational Approaches to Lipophilicity 19512.1.1 Introduction 19512.1.2 Limits of Fragmental Systems 19612.2 The Molecular Lipophilicity Potential (MLP): a Tool to Compute

Partition Coefficients from 3D Structures 19612.2.1 Derivation of the MLP 19612.2.2 Back-Calculation of Partition Coefficient 19712.3 The MLP: a Tool to Explore Conformational Effects on

Lipophilicity 19812.3.1 Quenched Molecular Dynamics: an Effective Exploration of

Conformational Space 19812.3.2 Conformation-Dependent Variations in Lipophilicity as Described by

the MLP 19912.3.3 Applications 20012.3.3.1 Lipophilicity Variation in GABA-receptor Antagonists 20012.3.3.2 Lipophilicity of L-Dopa Esters 20212.4 The MLP as a Docking Tool 20412.4.1 Intrinsic MLP, Perceived MLP, and Similarities Between Them . . . 20412.4.2 Applications 20412.4.2.1 Binding Modes of some D2-receptor Agonists 20412.4.2.2 Binding Modes of HEL (52-61) to the I-Ak MHC II Protein . . . . 20612.5 The MLP as an Additional Field in 3D QSAR 20812.5.1 Limits of Standard CoMFA Approaches 20812.5.2 The MLP, a Third Field in CoMFA 20912.5.2.1 Theory 20912.5.2.2 Intercorrelations of CoMFA Results Obtained with

Different Fields 210

XX Contents

12.5.3 Applications 21112.5.3.1 Binding to 5-HTIA Receptors 21112.5.3.2 CoMFA Models of Sweetness in Halogenated Sucroses 21312.6 Perspectives 214

Acknowledgements 215References 215Appendix 217

13 Hydrophobic Fields in Quantitative Structure-ActivityRelationships 219G. Folkers and A. Merz

13.1 Introduction . 21913.2 Definition 22013.3 Fragmental Property Contributions 22113.4 Algorithms for Calculation of Hydrophobic Fields 22213.4.1 GRID 222

,13.4.2 Molecular Lipophilicity Potential (MLP) 22313.4.3 Hydrophobic Interaction Potential (HINT) 22313.5 Combination of Hydrophobic Fields with 3D QSAR Techniques . . 22413.6 Mechanistic Interpretation of Protein-Ligand Crystal Data 22413.7 YAK 22513.8 Experiments and Caveats 22613.9 Outlook 230

References 231

14 Physico-Chemical and Biological Factors that Influence aDrug's Cellular Permeability by Passive Diffusion 233R. A. Conradi, P. S. Burton and R. T. Borchardt

14.1 Introduction 23314.1.1 Cellular Barriers to Drug Transport 23414.1.2 Transport Pathways 23514.1.2.1 Paracellular Transport 23514.1.2.2 Transcellular Transport 23614.2 Physico-Chemical Factors Influencing Transcellular Passive Diffusion 23714.2.1 Predictive Partition Coefficients 24014.2.2 Relationship to a Drug's Lipophilicity 24114.2.3 Relationship to a Drug's Hydrogen Bonding Potential 24214.2.3.1 Intestinal Mucosal Cell Transport 24214.2.3.2 Blood-Brain Barrier Transport 24514.2.3.3 Mechanistic Considerations 24514.2.4 Relationship to a Drug's Solution Conformation 24614.3 Biological Factors Influencing Transcellular Passive Permeability:

Polarized Efflux Systems 24714.4 Rationally Designing Drugs with Enhanced Cellular Permeability . 249

Acknowledgements 249References 250

Contents XXI

15 Lipophilicity of Metabolites and Its Role inBiotransformation 253B. Walther, P. Vis and A. Taylor

15.1 Introduction 25315.2 Introduction of a Lipophilic Group into a Drug 25415.3 Introduction of a Polar Group into a Drug 25615.3.1 Increase of Lipophilicity Following a Phase 1 Reaction 25615.3.2 Increase of Lipophilicity Following a Phase 2 Reaction 25715.4 Pharmacokinetic and Pharmacodynamic Consequences 259

References 261

16 The Role of Lipophilicity in Biological Response to Drugs andEndogenous Ligands 263V. Pliska

16.1 Introductory Comments and Definitions 26516.2 Phases of a Biological Response 26616.3 Stimulus-Response Profiles 26716.3.1 Characteristic Types of Response Profiles 26716.3.2 Time and Intensity Components of a Response 26916.4 Bioactive Substance in the Receptor Compartment:

Response Function 26916.4.1 General Formula of the Response Function 26916.4.2 Transport and Partitioning 27016.4.3 Compartmentation in the Vicinity of a Membrane 27116.4.4 Partitioning in the Aqueous/Lipid Interphase on Cell Surface 27216.5 Ligand-Receptor Interaction 27416.6 Factors Determining Biological Responses: a Summary 27716.7 Partial Agonism and the Role of Lipophilicity 27716.7.1 Dose-Response Relationship and the Phenomenon of

"Partial Agonism" 27716.7.2 Partial Agonism in Cholinergic Systems 27916.7.3 Molecular Perturbation Hypotheses 28016.7.4 "Wrong-Way" Binding Model of Partial Agonism 28016.7.5 Effect of Lipophilicity on Intrinsic Activity 28116.7.6 Other Examples of Full-to-Partial-Agonism Transition due to

Lipophilicity Increase 28216.8 Bell-Shaped Dose-Response Curves 28316.9 Thermodynamic Aspects of Variable Intrinsic Activity 28516.9.1 Hydrophobic Interactions as an Entropy-Driven Process 28516.9.2 AS °, AH ° Relationships in Some Receptor Systems 28616.9.2.1 Muscarinic Receptors 28616.9.2.2 |3-Adrenergic Receptors 28716.9.2.3 GABAA Receptors 28916.9.2.4 Opioid Receptors 289

XXII Contents

16.9.2.5 Adenosine A! Receptors 28916.9.2.6 Dopamine D2 Receptors 29016.9.3 Entropy-Enthalpy Compensation 29016.10 Outlook 291

References 291

17 Membrane Transport and Cellular Distribution 295S. Baldz

111 Introduction 29617.2 Model 29717.2.1 Model Construction 29717.2.2 Relation Between Individual Distribution Processes and

Drug Properties 29817.2.2.1 Transport Through Phase Interface 29817.2.2.2 Membrane Accumulation 29917.2.2.3 Binding to Cell Constituents 29917.2.2.4 Enzymatic and Spontaneous Reactions 29917.3 Numerical Simulations 30017.3.1 Closed Systems 30217.3.1.1 Nonequilibrium Period 30217.3.1.2 Equilibrium Period 30317.3.1.3 Mixed Period 30317.3.2 Open Systems 30317.4 Explicit Descriptions 30417.4.1 Nonionizable Compounds 30517.4.2 Ionizable Compounds 30617.4.3 Varying Acidity of the External Medium 30717.5 Outlook 307

Acknowledgements 307References 308

18 Applications of a Solvation Equation to Drug TransportProperties 311M. H. Abraham and H. S. Chadra

18.1 Introduction 31218.2 The Determination of Descriptors 31518.3 Applications of the Solvation Equation 32418.3.1 Seller's Alog P Parameter 32518.3.2 Reversed-phase HPLC 32618.3.3 Water/Micelle Partition 32718.3.4 The Blood-brain Barrier 32818.3.5 Permeation Through Skin 33118.4 Conclusions 335

References 335

Contents XXIII

19 Environmental Hazard Assessment Using Lipophilicity Data 339R. L. Lipnick

19.1 Introduction 33919.2 Historical Perspective 34019.2.1 Nonlinear Relationship to Water Solubility 34019.2.2 Relationship of Toxicity to Chain Length and Molecular Weight . . . 34019.2.3 Chemical Constitution Theory of Hypnotic Activity 34119.2.4 Richet'sLaw 34119.2.5 Development of the Lipoid Theory of Narcosis 34119.2.6 QSAR and More Quantitative Use of Lipophilicity Data 34219.3 Toxicological Applications 34219.3.1 Contributions of Lazarev 34219.3.2 Development of QSAR in Aquatic Toxicology 34419.3.3 Water Solubility and Pharmacokinetic Cutoff: QSAR Limitations . 34519.3.4 Additive Effects of Toxicants 34519.3.5 Bioconcentration 34619.3.6 Thermodynamic Approaches 34719.3.7 Excess Toxicity as a Measure of Specific Mechanism of Action . . . 34719.3.7.1 Electrophile Toxicants 34819.3.7.2 Proelectrophile Toxicants 34819.3.7.3 CyanogenicToxicants 34919.4 Biodegradation 35019.5 Outlook 350

References 351

20 Lipophilicity in Peptide Chemistry and Peptide Drug Design 355J.-L. Fauchere

20.1 Introduction 35520.2 Lipophilicity of Amino Acids and Parametrization of Side Chain

Hydrophobicity 35620.3 Lipophilicity of Pep tides, Pseudopeptides and Mimetics 35820.3.1 Experimental P Values for Pep tides 35820.3.2 Calculated Values of log P (log D) for Peptides 36020.3.3 Pseudopeptides 36220.3.4 Peptidomimetics 36320.4 Lipophilicity and Peptide Conformation 36420.4.1 Log P and Conformation 36420.4.3 Amphipathic Secondary Structures 36520.4.4 Hydrophobic Collapse 36520.4.5 Molecular Lipophilicity Potential 36620.5 Lipophilicity and Peptide Transport 36620.5.1 Pharmacokinetic Properties 36620.5.2 Hydrogen Bonding and Hydrophobicity 366

XXIV Contents

20.5.3 Prodrugs 36820.6 Conclusion and Outlook 369

References 370

21 Side Chain Lipophilicity of Noncoded a-Amino Acids:^r-Values 375V. Pliska and E. Escher

21.1 Introduction 37521.2 Lipophilicity Descriptor n 37621.3 Description of Tables 37621.4 Newly Reported j/r-values 37721.5 Tables 378

References 386

22 The Application of the Intermolecular Force Model toBioactivity, Peptide and Protein Quantitative Structure-ActivityRelationships 387M. Charton

22.1 Introduction 38722.1.1 The Intermolecular Force (IMF) Equation 38822.1.1.1 Intermolecular Force Parameterization 38822.1.1.2 Steric Effect Parameterization 38922.1.2 The Composition of the Side Chain Effect 39022.1.3 The IMF Equation for Peptide and Protein Bioactivity 39022.2 The IMF Method as a Bioactivity Model 39022.2.1 The Hansch-Fujita Model 39022.2.2 Alternatives to the Use of Lipophilicity Parameters 39222.3 Bioactivity Model 39222.4 Peptide Bioactivities 39422.4.1 Types of Structural Variation in Peptides 39422.4.2 Peptide QSARs 39522.5 Protein Bioactivities 39722.5.1 Types of Protein Bioactivity Data Sets 39722.5.2 Protein QSAR 39822.5.3 Limitation of the Model in Protein QSAR 398

References 399

23 Lipophilicity Descriptors for Structure-Property CorrelationStudies: Overview of Experimental and Theoretical Methodsand a Benchmark of log P Calculations 401H. van de Waterbeemd and R. Mannhold

23.1 Introduction 40223.2 Experimental Lipophilicity Scales 402

Contents XXV

23.2.1 Shake-Flask Partitioning 40223.2.1.1 Solvent/Water Systems 40223.2.1.2 Aqueous Biphasic Systems 40323.2.2 Chromatographic Methods 40323.2.2.1 RP-TLC 40323.2.2.2 RP-HPLC 40423.2.2.3 CPC 40423.2.3 Alternative Experimental Methods 40423.2.3.1 Slow Stirring 40423.2.3.2 Filter Probe and Filter Chamber 40523.2.3.3 Flow-Injection Extraction 40523.2.3.4 Microscale Partitioning Apparatus 40523.2.3.5 pH-Metric log P Determination 40523.3 Calculated log P values 40523.3.1 Overview 40523.3.1.1 The jr-System 40523.3.2 ALOGP Methods 40623.3.2.1 Calculation Method According to Ghose-Crippen 40623.3.2.2 The HINT Approach of Abraham 40723.3.2.3 The SMILOGP Approach of Dubost 40723.3.3 BLOGP Methods 40723.3.3.1 Conformation-Dependent log P calculations 40823.3.4 CLOGP Methods 40823.3.4.1 The 2f System of Rekker 40823.3.4.2 CLOGP System of Hansch and Leo 40823.3.4.3 Calculation Method According to Suzuki and Kudo 40923.3.4.4 The CASE KLOGP Method 40923.4 Comparison of log P Calculation Methods 40923 A.I A Benchmark of Simple Organic Compounds and Drugs 41023.4.1.1 General Remarks 41023.4.1.2 The Full Data Set 41023.4.1.3 Subsets: Drugs and Simple Organic Compounds 41123.5 Databases 41123.5.1 Log P Databases 41123.5.2 Substituent Values for Aliphatic and Aromatic Substituents 41323.5.3 Lipophilicity Scales for Amino Acids 41323.6 Perspectives 414

Acknowledgements 415References 415

Index 419