Thermodynamics and Kinetics of Drug Binding -  - ebook

Thermodynamics and Kinetics of Drug Binding ebook

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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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Table of Contents

Cover

Series

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Section I

Chapter 1: The Binding Thermodynamics of Drug Candidates

1.1 Affinity Optimization

1.2 The Binding Affinity

1.3 The Enthalpy Change

1.4 The Entropy Change

1.5 Engineering Binding Contributions

1.6 Lipophilic Efficiency and Binding Enthalpy

Acknowledgments

References

Chapter 2: van't Hoff Based Thermodynamics

2.1 Relevance of Thermodynamics to Pharmacology

2.2 Affinity Constant Determination

2.3 The Origin of van't Hoff Equation

2.4 From van't Hoff toward Thermodynamic Discrimination

2.5 Representation of Δ

G

°, Δ

H

°, and Δ

S

° Data

2.6 The Adenosine Receptors Binding Thermodynamics Story

2.7 Binding Thermodynamics of G-Protein Coupled Receptors

2.8 Binding Thermodynamics of Ligand-Gated Ion Channel Receptors

2.9 Discussion

Abbreviations

References

Chapter 3: Computation of Drug-Binding Thermodynamics

3.1 Introduction

3.2 Potential of Mean Force Calculations

3.3 Alchemical Transformations

3.4 Nonequilibrium Methods

3.5 MM-PBSA

3.6 Linear Interaction Energy

3.7 Scoring Functions

3.8 Free-energy Components

3.9 Summary

References

Chapter 4: Thermodynamics-Guided Optimizations in Medicinal Chemistry

4.1 Introduction

4.2 The Thermodynamics of Medicinal Chemistry Optimizations

4.3 Selection of Suitable Starting Points

4.4 Thermodynamics Based Optimization Strategies

References

Chapter 5: From Molecular Understanding to Structure–Thermodynamic Relationships, the Case of Acetylcholine Binding Proteins

5.1 Introduction

5.2 Acetylcholine Binding Proteins (AChBPs)

5.3 Thermodynamics of Small Molecule Binding at AChBPs

5.4 Concluding Remarks and Outlook

References

Chapter 6: Thermodynamics in Lead Optimization

6.1 Introduction to Lead Optimization in Drug Discovery

6.2 Measurement of Thermodynamic Parameters in Lead Optimization

6.3 Advantages during Lead Optimization for Thermodynamic Measurements

6.4 Exploitation of Measured Thermodynamics in Lead Optimization

6.5 Lead Optimization beyond Affinity

6.6 Exemplary Case Studies

6.7 Potential Complicating Factors in Exploiting Thermodynamics in Lead Optimization

6.8 Summary

References

Chapter 7: Thermodynamic Profiling of Carbonic Anhydrase Inhibitors

7.1 Introduction

7.2 Thermodynamic Profiles of Fragment Inhibitors

7.3 Thermodynamics of Fragment Growing

7.4 Conclusions

Acknowledgments

References

Section II

Chapter 8: Drug–Target Residence Time

8.1 Introduction

8.2 Open and Closed Systems in Biology

8.3 Mechanisms of Drug–Target Interactions

8.4 Impact of Residence Time on Cellular Activity

8.5 Impact on Efficacy and Duration

In vivo

8.6 Limitations of Drug–Target Residence Time

8.7 Summary

References

Chapter 9: Experimental Methods to Determine Binding Kinetics

9.1 Introduction

9.2 Definitions

9.3 Experimental Strategy

9.4 Experimental Methodologies

9.5 Specific Issues

9.6 Conclusion

Acknowledgment

References

Chapter 10: Challenges in the Medicinal Chemical Optimizationof Binding Kinetics

10.1 Introduction

10.2 Challenges

10.3 Optimization in Practice

10.4 Summary and Conclusions

References

Chapter 11: Computational Approaches for Studying Drug Binding Kinetics

11.1 Introduction

11.2 Theoretical Background

11.3 Model Types and Force Fields

11.4 Application Examples

11.5 Summary and Future Directions

Acknowledgments

References

Chapter 12: The Use of Structural Information to Understand Binding Kinetics

12.1 Introduction

12.2 Binding Kinetics

12.3 Methods to Obtain Structural Information to Understand Binding Kinetics

12.4 Literature on Structure Kinetic Relationships

12.5 Current Thinking on the Structural Factors That Influence Binding Kinetics

12.6 Concluding Remarks

References

Chapter 13: Importance of Drug–Target Residence Time at G Protein-Coupled Receptors – a Case for the Adenosine Receptors

13.1 Introduction

13.2 The Adenosine Receptors

13.3 Mathematical Definitions of Drug–Target Residence Time

13.4 Current Kinetic Radioligand Assays

13.5 Dual-Point Competition Association Assay: a Fast and High-Throughput Kinetic Screening Method

13.6 Drug–Target Residence Time: an Often Overlooked Key Aspect for a Drug's Mechanism of Action

13.7 Conclusions

Acknowledgments

References

Chapter 14: Case Study: Angiotensin Receptor Blockers (ARBs)

14.1 Introduction

14.2 Insurmountable Antagonism

14.3 From Partial Insurmountability to an Induced Fit-Binding Mechanism

14.4 Sartan Rebinding Contributes to Long-Lasting AT

1

-Receptor Blockade

14.5 Summary and Final Considerations

References

Chapter 15: The Kinetics and Thermodynamics of Staphylococcus aureus FabI Inhibition

15.1 Introduction

15.2 Fatty Acid Biosynthesis as a Novel Antibacterial Target

15.3 Inhibition of saFabI

15.4 Computer-Aided Enzyme Kinetics to Characterize saFabI Inhibition

15.5 Orthogonal Methods to Measure Drug–Target Residence Time

15.6 Mechanism-Dependent Slow-Binding Kinetics

15.7 Mechanistic Basis for Binary Complex Selectivity

15.8 Rational Design of Long Residence Time Inhibition

15.9 Summary

References

Section III

Chapter 16: Thermodynamics and Binding Kinetics in Drug Discovery

16.1 Introduction

16.2 Reaction Coordinate

16.3 Competing Rates

16.4 Thermodynamic Controlled Process – Competing Rates under Equilibrium Conditions

16.5 Kinetics Controlled Processes – Competing Rates under Non-equilibrium Conditions

16.6 Conformational Controlled Process – Kinetics as a Diagnostic for Conformational Change

16.7 The Value of Thermodynamics Measurements to Drug Discovery

16.8 Complementarity of Binding Kinetics and Thermodynamic to Discover Safer Medicines

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

A Personal Foreword

Section I: Thermodynamics

Begin Reading

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 1.4

Figure 1.5

Figure 1.6

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 3.1

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 4.8

Figure 4.9

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.5

Figure 5.6

Figure 5.7

Figure 5.8

Figure 5.9

Figure 5.10

Figure 5.11

Figure 5.12

Figure 6.1

Figure Scheme 6.1

Figure 6.2

Figure 6.3

Figure Scheme 6.2

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 7.8

Figure 7.9

Figure 8.1

Figure 8.2

Figure 8.3

Figure Scheme 9.2

Figure Scheme 9.1

Figure 9.1

Figure 9.2

Figure 9.3

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 10.12

Figure 10.13

Figure 10.14

Figure 10.15

Figure 10.16

Figure 10.17

Figure 10.18

Figure 11.1

Figure 11.2

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 12.6

Figure 12.7

Figure 12.8

Figure 12.9

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 14.1

Figure 14.2

Figure 14.3

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 15.5

Figure 15.7

Figure 15.6

Figure 15.8

Figure 15.9

Figure 15.10

Figure 16.1

Figure 16.2

Figure 16.3

Figure 16.4

Figure 16.5

Figure 16.6

Figure 16.7

List of Tables

Table 1.1

Table 2.1

Table 2.2

Table 2.3

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Table 5.1

Table 5.2

Table 7.1

Table 8.1

Table 9.1

Table 12.1

Table 13.1

Table 13.2

Table 15.1

Table 16.1

Table 16.2

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board:

H. Buschmann, H. Timmerman, H. van de Waterbeemd

Previous Volumes of this Series:

Pfannkuch, Friedlieb / Suter-Dick, Laura (Eds.)

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From Vision to Reality

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Vol. 62

Liras, Spiros / Bell, Andrew S. (Eds.)

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Vol. 61

Hanessian, Stephen (Ed.)

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ISBN: 978-3-527-33218-2

Vol. 60

Lackey, Karen / Roth, Bruce (Eds.)

Medicinal Chemistry Approaches to Personalized Medicine

2013

ISBN: 978-3-527-33394-3

Vol. 59

Brown, Nathan (Ed.)

Scaffold Hopping in Medicinal Chemistry

2013

ISBN: 978-3-527-33364-6

Vol. 58

Hoffmann, Rémy / Gohier, Arnaud / Pospisil, Pavel (Eds.)

Data Mining in Drug Discovery

2013

ISBN: 978-3-527-32984-7

Vol. 57

Dömling, Alexander (Ed.)

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2013

ISBN: 978-3-527-33107-9

Vol. 56

Kalgutkar, Amit S. / Dalvie, Deepak / Obach, R. Scott / Smith, Dennis A.

Reactive Drug Metabolites

2012

ISBN: 978-3-527-33085-0

Vol. 55

Edited by György M. Keserü and David C. Swinney

Thermodynamics and Kinetics of Drug Binding

Series Editors

Prof. Raimund Mannhold

Rosenweg 7

40489 Düsseldorf

Germany

[email protected]

Prof. Hugo Kubinyi

Donnersbergstrasse 9

67256 Weisenheim am Sand

Germany

[email protected]

Prof. Gerd Folkers

Collegium Helveticum

STW/ETH Zurich

8092 Zurich

Switzerland

[email protected]

Volume Editors

Prof. Dr. György M. Keserü

Research Centre for Natural Sciences

Hungarian Academy of Sciences

Magyar tudósok körútja 2

1117 Budapest

Hungary

Dr. David C. Swinney

Institute for Rare and Neglected Diseases Drug Discovery

897 Independence Ave.

Mountain View, CA 94043

USA

Cover

The cover picture was created from a crystal structure of the heat shock protein 90 (HSP90) cocrystallyzed with the ligand of 4-CHLORO-6-(2-METHOXYPHENYL)PYRIMIDIN-2-AMINE (PDB code: 2XDX) by Ákos Tarcsay. The structure is available at http://www.pdb.org/pdb/explore/explore. do?structureId=2XDX. More information on the ligand and the target is available in Murray, C.W., Carr, M.G., Callaghan,O., Chessari, G., Congreve,M., Cowan, S., Coyle, J.E., Downham, R., Figueroa, E., Frederickson, M., Graham,B., Mcmenamin, R., O'Brien, M.A., Patel, S., Phillips, T.R., Williams, G., Woodhead,A.J., Woolford, A.J.A. (2010) J. Med. Chem. 53, 5942 – 5955.

PubMed: 20718493 DOI: 10.1021/jm100059d

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List of Contributors

Eleanor K. H. Allen

Stony Brook University

Department of Chemistry

Institute for Chemical Biology and Drug Discovery

John S. Toll Drive

Stony Brook, NY 11794

USA

Pelin Ayaz

Bayer Healthcare Pharmaceuticals

Lead Discovery Berlin

Müllerstrasße 178

13353 Berlin

Germany

Antoni R. Blaazer

VU University Amsterdam

Division of Medicinal Chemistry

Faculty of Sciences

Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

Pier Andrea Borea

University of Ferrara

Department of Medical Sciences

Pharmacology section, via Fossato di Mortara 17-19

44121 Ferrara

Italy

Andrew Chang

Stony Brook University

Department of Chemistry

Institute for Chemical Biology and Drug Discovery

John S. Toll Drive

Stony Brook, NY 11794

USA

Robert A. Copeland

Epizyme, Inc.

400 Technology Square

4th Floor

Cambridge, MA 02139

USA

Gareth Davies

Structure and Biophysics

Discovery Sciences

AstraZeneca, Mereside

Alderley Park

Macclesfield

Cheshire SK10 4TG

UK

Iwan J. P. de Esch

VU University Amsterdam

Division of Medicinal Chemistry

Faculty of Sciences

Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)

De Boelelaan 1083

1081 HV Amsterdam

The Netherlands

György G. Ferenczy

Hungarian Academy of Sciences

Research Centre for Natural Sciences

Medicinal Chemistry Research Group

Magyar tudósok körútja 2

1117 Budapest

Hungary

Ernesto Freire

The Johns Hopkins University

Department of Biology

3400 North Charles

Baltimore, MD 21218

USA

Jonathan C. Fuller

Molecular and Cellular Modeling Group

Heidelberg Institute for Theoretical Studies

Schloss-Wolfsbrunnenweg 35

69118 Heidelberg

Germany

Stefania Gessi

University of Ferrara

Department of Medical Sciences

Pharmacology section, via Fossato di Mortara 17-19

44121 Ferrara

Italy

Dong Guo

Leiden University

Department of Medicinal Chemistry

Einsteinweg 55

2333CC Leiden

The Netherlands

Laura H. Heitman

Leiden University

Department of Medicinal Chemistry

Einsteinweg 55

2333CC Leiden

The Netherlands

Geoffrey A. Holdgate

Structure and Biophysics

Discovery Sciences

AstraZeneca, Mereside

Alderley Park

Macclesfield

Cheshire SK10 4TG

UK

Walter Huber

F. Hoffmann-La Roche AG

Pharma Research and Early Development

Grenzacherstrasse 124

4070 Basel

Switzerland

Adriaan P. Ijzerman

Leiden University

Department of Medicinal Chemistry

Einsteinweg 55

2333CC Leiden

The Netherlands

Lyn H. Jones

Chemical Biology Group

WorldWide Medicinal Chemistry

Pfizer

610 Main Street

Cambridge, MA 02139

USA

Kanishk Kapilashrami

Stony Brook University

Department of Chemistry

Institute for Chemical Biology and Drug Discovery

John S. Toll Drive

Stony Brook, NY 11794

USA

György M. Keserü

Hungarian Academy of Sciences

Research Centre for Natural Sciences

Magyar Tudósok körútja 2

1117 Budapest

Hungary

Daria B. Kokh

Molecular and Cellular Modeling Group

Heidelberg Institute for Theoretical Studies

Schloss-Wolfsbrunnenweg 35

69118 Heidelberg

Germany

Andrew G. Leach

School of Pharmacy and Biomolecular Sciences

Liverpool John Moores University

Byrom Street

Liverpool

Merseyside L3 3AF

UK

Stefania Merighi

University of Ferrara

Department of Medical Sciences

Pharmacology section, via Fossato di Mortara 17-19

44121 Ferrara

Italy

Duncan C. Miller

Newcastle Cancer Centre

School of Chemistry

Newcastle University

Northern Institute for Cancer Research

Bedson Building

Newcastle upon Tyne NE1 7RU

UK

Anke Müller-Fahrnow

Bayer Healthcare Pharmaceuticals

Lead Discovery Berlin

Müllerstraße 178

13353 Berlin

Germany

Julia Romanowska

Molecular and Cellular Modeling Group

Heidelberg Institute for Theoretical Studies

Schloss-Wolfsbrunnenweg 35

69118 Heidelberg

Germany

Felix Schiele

Bayer Healthcare Pharmaceuticals

Lead Discovery Berlin

Müllerstraße 178

13353 Berlin

Germany

Andrew Scott

Molplex Ltd

BioHub @ Alderley Park

Macclesfield

Cheshire SK10 4TG

UK

David C. Swinney

Institute for Rare and Neglected Diseases Drug Discovery

897 Independence Ave

Suite 2C

Mountain View, CA 94043

USA

Peter J. Tonge

Stony Brook University

Department of Chemistry

Institute for Chemical Biology and Drug Discovery

John S. Toll Drive

Stony Brook, NY 11794

USA

Katia Varani

University of Ferrara

Department of Medical Sciences

Pharmacology section, via Fossato di Mortara 17-19

44121 Ferrara

Italy

Georges Vauquelin

Vrije Universiteit Brussel

Department of Molecular and Biochemical Pharmacology

Pleinlaan 2

1050 Brussels

Belgium

Rebecca C. Wade

Molecular and Cellular Modeling Group

Heidelberg Institute for Theoretical Studies

Schloss-Wolfsbrunnenweg 35

69118 Heidelberg

Germany

and

Heidelberg University

Center for Molecular Biology (ZMBH)

DKFZ-ZMBH Alliance and Interdisciplinary

Center for Scientific Computing (IWR)

Im Neuenheimer Feld 282

69120 Heidelberg

Germany

Michael J. Waring

Oncology Medicinal Chemistry

AstraZeneca

Mereside

Alderley Park

Macclesfield

Cheshire SK10 4TG

UK

Preface

In the realm of modern medicine, therapy has become molecular. Understanding and defining the requirements of how a molecular signal is transmitted to cellular chemistry is mainly based on the understanding of the thermodynamics, which governs the journey of the active compound and its interaction with a binding site. The whole field is defined by two remarkably simple, but remarkably true sentences:

Corpora non agunt nisi liquida

(Paracelsus)

Corpora non agunt nisi fixata

(Paul Ehrlich)

In between those two fundamental concepts, much of the content of the present volume, edited by György Keserü and David Swinney, is located. The thermodynamic perspective of drug action is complex, difficult to be accessed experimentally, and intellectually not easily managed. These are reasons why the whole topic has always been a little bit neglected under the shiny glaze of colorful animated ligands dancing with their receptors.

Switching from “maximizing” affinities in screening campaigns to “optimizing” it requires a deep understanding of the enthalpic and entropic interplay between ligand and receptor. And to make the scenario a little bit more complicated, ligand and its receptor are not alone! Their context provides all kinds of interferences, starting off with “water” and its delicate contribution to binding, going to the membrane, many receptors that are positioned in. Membranes may not only stabilize (or destabilize) conformations of the receptor protein, they also offer secondary binding sites, where ligands may be conformationally preselected to interact with their molecular target: not to talk about membrane traveling peptides in switch control of the receptor proteins or counterions and so on.

It is important to emphasize that this is only one side of the coin. The whole binding process has its kinetic perspective as well. How long, for instance, a drug molecule resides at the binding site is of utmost importance to know for translation into the clinics.

The rich collection of chapters presented in this book touches many of those problems and comes in two parts to cover thermodynamics in the first part and kinetics in the second part. It has the merit of doing this with the perspective of application because this is a “handbook series.” Hence, we learn in addition to some theoretical excursions a lot from case studies and very practical descriptions of how to approach reliable binding parameters experimentally, discern enthalpic and entropic parts, and transfer this knowledge into practical design by selecting a proper substituent located at the proper site of the ligand.

Not least because of this, the series editors are indebted to György Keserü and David Swinney as well as the chapter authors, who made it possible to cover this very essential issue.

We are as well very much indebted to Heike Nöthe, Waltraud Wüst, and Frank Weinreich, all at Wiley-VCH. Their support and ongoing engagement, not only for this book but also for the whole series Methods and Principles in Medicinal Chemistry, adds to the success of this excellent collection of monographs on various topics, all related to drug research.

December 2014

Gerd Folkers, Zürich

Hugo Kubinyi, Weisenheim am Sand

Raimund Mannhold, Düsseldorf

A Personal Foreword

There are many aspects of drug discovery that can be addressed to increase its lower than expected productivity. Understanding the thermodynamics and kinetics of drug action can provide opportunities to help identify effective new medicines and increase productivity. Drug action begins with an interaction of medicines with physiological proteins, known as drug targets. This interaction initiates a series of molecular events that must ultimately communicate a safe, therapeutically useful pharmacological response that corrects the pathophysiology. The molecular details of the response are, in part, dependent on the thermodynamics and binding kinetics.

Although Paul Erlich received the 1908 Nobel Prize for Physiology or Medicine for his contribution to immunology, one of the most impactful results of the father of chemotherapy is summarized in his famous maxim “Corpora non agunt nisi fixata,” which translated becomes – a substance is not (biologically) active unless it is “fixed” (bound to a biological macromolecule) in 1913. The formation of a ligand–macromolecule complex, often qualitatively described as the process of molecular recognition, is typically realized by specific interactions between the partners. Designing, understanding, and improving these interactions require quantitative measures that describe the energetics of complex formation. Binding thermodynamics that governs the process of molecular recognition has therefore a key role in characterizing and optimizing ligand–target interactions, and consequently, its exploitation might contribute to more efficient design of new medicines.

From a thermodynamic perspective, the main driving force of the formation of the ligand–target complex is the change in free energy of binding (ΔG). Since ΔG has two components, the binding enthalpy (ΔH) and the binding entropy (ΔS), one can improve ΔG both enthalpically and entropically. Recent efforts collected to the thermodynamic section of this book are trying to rationalize enthalpic and entropic contributions of ligand binding. Here, we first introduce the methodologies available for the evaluation of binding thermodynamics that include isothermal titration calorimetry, van't Hoff analysis, and computational approaches. The next chapter focuses on uncovering structure–thermodynamics relationship that is one of the most challenging parts of thermodynamics based on lead discovery and optimization. Finally, the authors coming from real-life drug discovery settings discuss the impact of binding thermodynamics studies on drug discovery programs.

Evaluation of binding thermodynamics contributes many aspects of drug discovery. Early-phase discovery programs might benefit identifying chemical starting points with enthalpy-driven binding. Fragment-based drug discovery is a typical example of this approach, demonstrating that the binding of most fragment hits is enthalpy driven. Later phase programs might utilize thermodynamic characterization when selecting compounds at milestones such as the identification of lead molecules, advanced leads, and development candidates. There is increasing evidence that binding thermodynamics influences not only the binding affinity but also selectivity, specificity, and drug-like properties. Considering all of these factors, we can conclude that thermodynamic characterization of discovery compounds might contribute to improving compound quality, and therefore could help making the preclinical phase of drug discovery more productive.

The importance of kinetics to a response has long been recognized. The concept of binding kinetics dates back to work in the 1960s by William Paton, one of the pioneers of pharmacology. In one paper, Paton postulated a rate theory, which uses the interaction of a drug with its receptor to explain drug action, potency, and speed of offset. Recent retrospective analyses have proposed that a drug's dissociation rate from the receptor, koff, also known as residence time, 1/koff, is associated with the evolution of optimal efficacy, safety, and drug use within therapeutic classes. A greater understanding of binding kinetics may create opportunities for more efficient optimization of molecules into medicines.

To evaluate and exploit potential opportunities, a number of questions have to be addressed. Of primary importance to medicinal chemists is the understanding of structure–kinetic relationships (SKR) and how binding kinetics translates to clinical utility. This will be enabled by reliable assays and systematic analysis of SKRs. They will help address questions of can binding kinetics be optimized prospectively? And, can we predict how kinetics will translate to clinical responses. To date, there are few reports of systematic analysis of SKR to inform design principles, and there is uncertainty how to realize the full value of binding kinetics.

The study and use of binding kinetics is currently getting more attention as evidenced by its inclusion in this book series. The understanding of binding kinetics, the opportunities, and the value are evolving. Binding kinetics has the potential to impact many aspects of drug discovery, pharmacology, and medicine. First, the increased awareness of the role of time-dependent processes and dynamics will inform experimental design and interpretation. Medical researchers from all disciplines will be empowered by thinking in terms of kinetics in addition to equilibrium thermodynamics. Second, we think that further understanding of the molecular features governing association and dissociation of a drug with its target will facilitate rational drug design and understanding the molecular mechanisms of drug action. It is clear that the equilibrium dissociation constant can be influenced by both kon and koff. Third, understanding binding kinetics has the potential to better inform clinical pharmacology and understanding and optimizing PK/PD relationships. And last, binding kinetic has the potential to increase productivity by contributing to an optimal therapeutic index. A better understanding of how to early predict and optimize binding kinetics to provide an optimal therapeutic index should help decrease attrition in clinical studies. For example, medicines that have the potential for mechanism-based toxicity may benefit from fast off rates, whereas medicines without the potential for mechanism-based toxicity may benefit for very slow off rates that create irreversible/insurmountable pharmacological behavior.

Addressing both the thermodynamic and kinetic aspects of ligand binding provides opportunities for medicinal chemistry, computational chemistry, computational biology, structural chemistry and biology, analytical chemistry, and pharmacology. Clarity on first principles, methods of analysis, medicinal chemistry design, and translation to clinical pharmacology are all important. To this end, leaders in the study of binding thermodynamics and kinetics have contributed chapters that describe their current understandings. It is clear from the breadth of examples that binding thermodynamics and kinetics are an important features of drug action, and that there are many opportunities to further understand and use them in drug discovery. The challenge is to prospectively apply the knowledge to maximize the value of the opportunities.

We would like to acknowledge to all contributing authors for sharing their knowledge and perspective on the thermodynamic and kinetic aspects of ligand binding, we thank the series editors Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers for the opportunity addressing the topic, and Frank Weinreich, Gregor Cicchetti, and Waltraud Wuest at Wiley-VCH for their support and commitment.

December 2014

György M. Keserű

Hungary

David C. Swinney

USA

Section I

Thermodynamics

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