Protein-Ligand Interactions E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 735

Veröffentlichungsjahr: 2012

Beschreibung

Innovative and forward-looking, this volume focuses on recent achievements in this rapidly progressing field and looks at future potential for
development.
The first part provides a basic understanding of the factors governing protein-ligand interactions, followed by a comparison of key experimental methods (calorimetry, surface plasmon resonance, NMR) used in generating interaction data. The second half of the book is devoted to insilico methods of modeling and predicting molecular recognition and binding, ranging from first principles-based to approximate ones. Here,
as elsewhere in the book, emphasis is placed on novel approaches and recent improvements to established methods. The final part looks at
unresolved challenges, and the strategies to address them.
With the content relevant for all drug classes and therapeutic fields, this is an inspiring and often-consulted guide to the complexity of
protein-ligand interaction modeling and analysis for both novices and experts.

Leseprobe

Contents

Cover

Series Page

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Part I: Binding Thermodynamics

Chapter 1: Statistical Thermodynamics of Binding and Molecular Recognition Models

1.1 Introductory Remarks

1.2 The Binding Constant and Free Energy

1.3 A Statistical Mechanical Treatment of Binding

1.4 Strategies for Calculating Binding Free Energies

References

Chapter 2: Some Practical Rules for the Thermodynamic Optimization of Drug Candidates

2.1 Engineering Binding Contributions

2.2 Eliminating Unfavorable Enthalpy

2.3 Improving Binding Enthalpy

2.4 Improving Binding Affinity

2.5 Improving Selectivity

2.6 Thermodynamic Optimization Plot

Acknowledgments

References

Chapter 3: Enthalpy–Entropy Compensation as Deduced from Measurements of Temperature Dependence

3.1 Introduction

3.2 The Current Status of Enthalpy–Entropy Compensation

3.3 Measurement of the Entropy and Enthalpy of Activation

3.4 An Example

3.5 The Compensation Temperature

3.6 Effect of High Correlation on Estimates of Entropy and Enthalpy

3.7 Evolutionary Considerations

3.8 Textbooks

References

Part II: Learning from Biophysical Experiments

Chapter 4: Interaction Kinetic Data Generated by Surface Plasmon Resonance Biosensors and the Use of Kinetic Rate Constants in Lead Generation and Optimization

4.1 Background

4.2 SPR Biosensor Technology

4.3 From Interaction Models to Kinetic Rate Constants and Affinity

4.4 Affinity versus Kinetic Rate Constants for Evaluation of Interactions

4.5 From Models to Mechanisms

4.6 Structural Information

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

4.8 Designing Compounds with Optimal Properties

4.9 Conclusions

Acknowledgments

References

Chapter 5: NMR Methods for the Determination of Protein–Ligand Interactions

5.1 Experimental Parameters from NMR

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

5.3 Ligand-Induced Conformational Changes of a Cyclic Nucleotide Binding Domain [117, 118]

5.4 Ligand Binding to GABARAP: Binding Site and Affinity Mapping [61]

5.5 Transient Binding of Peptide Ligands to Membrane Proteins [108, 137]

References

Part III: Modeling Protein–Ligand Interactions

Chapter 6: Polarizable Force Fields for Scoring Protein–Ligand Interactions

6.1 Introduction and Overview

6.2 Amoeba Polarizable Potential Energy Model

6.3 Amoeba Explicit Water Simulation Applications

6.4 Implicit Solvent Calculation Using Amoeba Polarizable Force Field

6.5 Conclusions and Future Directions

References

Chapter 7: Quantum Mechanics in Structure-Based Ligand Design

7.1 Introduction

7.2 Three MM–Based Methods

7.3 QM-Based Force Fields

7.4 QM Calculations of Ligand Binding Sites

7.5 QM/MM Calculations

7.6 QM Calculations of Entire Proteins

7.7 Concluding Remarks

Acknowledgments

References

Chapter 8: Hydrophobic Association and Volume–Confined Water Molecules

8.1 Introduction

8.2 Water as a Whole in Hydrophobic Association

8.3 Confined Water Molecules in Protein–Ligand Binding

Acknowledgments

References

Chapter 9: Implicit Solvent Models and Electrostatics in Molecular Recognition

9.1 Introduction

9.2 Poisson–Boltzmann Methods

9.3 The Generalized Born Model

9.4 Reference Interaction Site Model of Molecular Solvation

9.5 Applications

Acknowledgments

References

Chapter 10: Ligand and Receptor Conformational Energies

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

10.2 Computational Results on Ligand Conformational Energy

10.3 Computational Results on Receptor Conformational Energy

10.4 Concluding Remarks

Acknowledgments

References

Chapter 11: Free Energy Calculations in Drug Lead Optimization

11.1 Modern Drug Design

11.2 Free Energy Calculations

11.3 Example Protocols and Applications

11.4 Discussion

References

Chapter 12: Scoring Functions for Protein–Ligand Interactions

12.1 Introduction

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

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

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

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

Acknowledgments

References

Part IV: Challenges in Molecular Recognition

Chapter 13: Druggability Prediction

13.1 Introduction

13.2 Druggability: Ligand Properties

13.3 Druggability: Ligand Binding

13.4 Druggability Prediction by Protein Class

13.5 Druggability Predictions: Experimental Methods

13.6 Druggability Predictions: Computational Methods

13.7 A Test Case: PTP1B

13.8 Outlook and Concluding Remarks

References

Chapter 14: Embracing Protein Plasticity in Ligand Docking

14.1 Introduction

14.2 Docking by Sampling Internal Coordinates

14.3 Fast Docking to Multiple Receptor Conformations

14.4 Single Receptor Conformation

14.5 Multiple Receptor Conformations

14.6 Improving Poor Homology Models of the Binding Pocket

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

14.8 Conclusions and Outlook

Acknowledgments

References

Chapter 15: Prospects of Modulating Protein–Protein Interactions

15.1 Introduction

15.2 Thermodynamics of Protein–Protein Interactions

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

15.4 Examples of CADD Applied to PPIs

15.5 Summary

Acknowledgments

References

Index

Methods and Principles in Medicinal Chemistry

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

Editorial Board

H. Buschmann, H. Timmerman, H. van

de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Kappe, C. Oliver / Stadler, Alexander /Dallinger, Doris

Microwaves in Organic and Medicinal Chemistry

Second, Completely Revised and Enlarged Edition

2012

ISBN: 978-3-527-33185-7

Vol. 52

Smith, Dennis A. / Allerton, Charlotte /

Kalgutkar, Amit S. / van de Waterbeemd, Han /

Walker, Don K.

Pharmacokinetics and Metabolism in Drug Design

Third, Revised and Updated Edition

2012

ISBN: 978-3-527-32954-0

Vol. 51

De Clercq, Erik (Ed.)

Antiviral Drug Strategies

2011

ISBN: 978-3-527-32696-9

Vol. 50

Klebl, Bert / Müller, Gerhard / Hamacher, Michael (Eds.)

Protein Kinases as Drug Targets

2011

ISBN: 978-3-527-31790-5

Vol. 49

Sotriffer, Christoph (Ed.)

Virtual Screening

Principles, Challenges, and Practical Guidelines

2011

ISBN: 978-3-527-32636-5

Vol. 48

Rautio, Jarkko (Ed.)

Prodrugs and Targeted Delivery

Towards Better ADME Properties

2011

ISBN: 978-3-527-32603-7

Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs, Rob (Eds.)

Chemokine Receptors as Drug Targets

2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases as Therapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead Profiling

Identification and Optimization of Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

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List of Contributors

Ruben AbagyanUniversity of California, San DiegoSkaggs School of Pharmacy andPharmaceutical Sciences9500 Gilman DriveLa Jolla, CA 92093USA

and

University of California, San DiegoSan Diego Supercomputer CenterLa Jolla, CA 92093USA

and

Molsoft LLC11199 Sorrento Valley Road, S209San Diego, CA 92121USA

Daniel Alvarez-GarciaUniversitat de BarcelonaFacultat de FarmàciaDepartament de FisicoquímicaAv. Joan XXIII s/n08028 BarcelonaSpain

and

Institut de Biomedicina de la Universitatde Barcelona (IBUB)BarcelonaSpain

Riccardo BaronThe University of UtahDepartment of Medicinal ChemistryCollege of Pharmacy

and

The Henry Eyring Center for Theoretical ChemistrySalt Lake CityUT 84112-5820USAEmail:[email protected]

Xavier BarrilUniversitat de BarcelonaFacultat de FarmàciaDepartament de FisicoquímicaAv. Joan XXIII s/n08028 BarcelonaSpain

and

Institut de Biomedicina de la Universitatde Barcelona (IBUB)BarcelonaSpain

and

Catalan Institution for Research andAdvanced Studies (ICREA)Passeig Lluís Companys 2308010 BarcelonaSpain

David A. CaseRutgers UniversityDepartment of Chemistry and ChemicalBiology and BioMaPS Institute610 Taylor RoadPiscataway, NJ 08854-8087USA

Athel Cornish-BowdenCNRSBioénergétique et Ingénierie des ProtéinesB.P. 71, 31 chemin Joseph-Aiguier13402 Marseille Cedex 20France

U. Helena DanielsonUppsala UniversityDepartment of Biochemistry andOrganic ChemistryBMC, Box 57675123 UppsalaSweden

Ernesto FreireJohns Hopkins UniversityDepartment of Biology114A Mudd Hall, 3400 North Charles StreetBaltimoreMD 21218-2685USA

Samuel GenhedenLund UniversityDepartment of Theoretical ChemistryChemical CentreP.O. Box 124221 00 LundSweden

Bernd W. KoenigForschungszentrum JülichIBI-252425 JülichGermany

Themis LazaridisCity University of New YorkCity College of New YorkDepartment of Chemistry138th Street & Convent AvenueNew York, NY 10031USA

Tyler LuchkoRutgers UniversityDepartment of Chemistry and ChemicalBiology and BioMaPS Institute610 Taylor RoadPiscataway, NJ 08854-8087USA

Alexander D. MacKerell Jr.University of Maryland BaltimoreSchool of PharmacyDepartment of Pharmaceutical Sciences20 Penn StreetBaltimore, MD 21201USA

J. Andrew McCammonUniversity of CaliforniaDepartment of Chemistry and BiochemistryCenter for Theoretical Biological PhysicsLa JollaCA 92093-0365USA

Taiji OashiUniversity of Maryland BaltimoreSchool of PharmacyDepartment of Pharmaceutical Sciences20 Penn StreetBaltimore, MD 21201USA

Pengyu RenThe University of Texas at AustinDepartment of Biomedical EngineeringBME 5.202M, 1 University Station, C0800AustinTX 78712-1062USA

Manuel RuedaUniversity of California, San DiegoSkaggs School of Pharmacy andPharmaceutical Sciences9500 Gilman DriveLa Jolla, CA 92093USA

Ulf RydeLund UniversityDepartment of Theoretical ChemistryChemical CentreP.O. Box 124221 00 LundSweden

Peter SchmidtkeUniversitat de BarcelonaFacultat de FarmàciaDepartament de FisicoquímicaAv. Joan XXIII s/n08028 BarcelonaSpainandInstitut de Biomedicina de la Universitatde Barcelona (IBUB)BarcelonaSpain

Sven SchünkeForschungszentrum JülichIBI-252425 JülichGermany

Jesus SecoUniversitat de BarcelonaFacultat de FarmàciaDepartament de FisicoquímicaAv. Joan XXIII s/n08028 BarcelonaSpain

and

Institut de Biomedicina de la Universitatde Barcelona (IBUB)BarcelonaSpain

Piotr SetnyTechnical University MunichDepartment of PhysicsMunichGermany

Paul ShapiroUniversity of Maryland BaltimoreSchool of PharmacyDepartment of Pharmaceutical Sciences20 Penn StreetBaltimore, MD 21201USA

Kim A. SharpUniversity of PennsylvaniaDepartment of Biochemistry and Biophysics37th and Hamilton WalkPhiladelphiaPA 19104-6059USA

Yue ShiThe University of Texas at AustinDepartment of Biomedical EngineeringBME 5.202M, 1 University Station, C0800AustinTX 78712-1062USA

Pär SöderhjelmETH ZürichDepartment of Chemistry and Applied BiosciencesComputational ScienceVia Giuseppe Buffi 136900 LuganoSwitzerland

Christoph SotrifferUniversity of WürzburgInstitute of Pharmacy and Food ChemistryDepartment of Pharmaceutical ChemistryAm Hubland97074 WürzburgGermany

Thomas SteinbrecherKarlsruher Institut für TechnologieInstitut für Physikalische ChemieGebäude 30.45, Kaiserstr. 1276131 KarlsruheGermany

Matthias StoldtForschungszentrum JülichIBI-252425 JülichGermany

Dieter WillboldForschungszentrum JülichIBI-252425 JülichGermany

Wenbo YuUniversity of Maryland BaltimoreSchool of PharmacyDepartment of Pharmaceutical Sciences20 Penn StreetBaltimore, MD 21201USA

Jiajing ZhangThe University of Texas at AustinDepartment of Biomedical EngineeringBME 5.202M, 1 University Station, C0800AustinTX 78712-1062USA

Shijun ZhongSchool of Life Science and TechnologyDalian University of Technology2 Linggong Road, DalianLiaoning Province, 116024, ChinaPhone: (086)0411-84707913 Email: [email protected],Email:[email protected]

Preface

“Um ein Bild zu gebrauchen, will ich sagen, dass Enzym und Glucosid wie Schloss und Schlüssel zueinander passen müssen, um eine chemische Wirkung aufeinander ausüben zu können” [To use a picture, I would like to say that enzyme and glucoside have to fit like a lock and a key, in order to exert a chemical action on each other] wrote Emil Fischer in 1894, to illustrate his concept on protein-ligand interactions. Well, our picture of the protein-ligand interaction has developed further. Instead of a rigid fit, the concepts of induced fit and, later, flexible fit were formulated. Indeed, we have to understand the interaction like a handshake, where the one partner adapts to the other, in a mutual fit. Of course, this accommodation should not waste too much conformational energy, otherwise the affinity of the ligand would be significantly reduced. Correspondingly experience shows that compounds where the bioactive conformation is fixed or at least stabilized are most often high-affinity ligands. On the other hand, ligands that cannot achieve such a conformation will have no affinity at all. However, these geometric requirements are only part of the story. In addition, there must be complementary properties - similia similibus. Lipophilic groups should find their counterpart, charges or partial charges should have opposite signs, and hydrogen bond donor and acceptor groups should find together. The better this complementarity, the higher will be the affinity, provided that there are no steric clashes. Now, whereas this is a correct description of the requirements of a protein-ligand interaction, it is a very simple one.

Holger Gohlke assembled a team of leading experts in this field to describe not only the thermodynamics of binding but also the underlying biophysical approaches. The major part of the book is devoted to the discussion of factors that are responsible for the intermolecular interactions. Finally some challenges in molecular recognition are discussed. In a logical and didactic way, this volume is organized in four sections. The three introductory chapters review statistical thermodynamics of binding and molecular recognition models, practical rules for the thermodynamic optimization of drug candidates, and the puzzling concept of enthalpy-entropy compensation, as deduced from measurements of temperature dependence. A section on the impact of biophysical experiments focuses, in particular, on interaction kinetic data generated by surface plasmon resonance biosensors as well as NMR methods for the determination of protein-ligand interactions. The central and most comprehensive section is dedicated to aspects of modeling protein-ligand interactions including polarizable force fields, quantum mechanics in structure-based ligand design, the role of water in hydrophobic association, implicit solvation models and electrostatics in molecular recognition, conformational aspects, free energy calculations in drug lead optimization, as well as scoring functions for protein-ligand interactions. The final section on challenges for protein-ligand interaction modelling considers druggability prediction, protein plasticity, and protein-protein interactions.

The series editors are grateful to Holger Gohlke for his enthusiasm to organize this volume and to work with such a selection of excellent authors. We believe that this book adds a fascinating new facet to our book series on “Methods and Principles in Medicinal Chemistry”. Last, but not least we thank the publisher Wiley-VCH, in particular Frank Weinreich and Heike Nöthe, for their valuable contributions to this project and the entire series.

February 2012DüsseldorfWeisenheim am SandZürich

Raimund MannholdHugo KubinyiGerd Folkers

A Personal Foreword

Ever since I started my scientific work I have been fascinated by the questions what makes two molecules bind to each other and how can one make use of this knowledge to modulate biological processes: After all, “corpora non agunt nisi fixata”, as Paul Ehrlich put it almost 100 years ago. Ehrlich's statement that “bodies do not act if they are not bound” is strikingly exemplified by about 130,000 binary interactions in the human protein-protein “interactome” [1]. Along the same lines and more oriented towards the topic of this book, the famous wall chart “Biochemical Pathways” introduced by Gerhard Michal [2] is a vivid picture in the eyes of a life science scientist, with its comprehensive view on metabolic pathways and cellular and molecular processes, particularly involving interactions between proteins and endogenous small-molecules.

For a xenobiotic ligand to exert an influence on an organism, it must bind to a biological target, too. While this statement seems unspectacular nowadays, it still has far-reaching consequences because it provides a valuable handle to explain and predict biological activity, both beneficial and detrimental, in terms of affinity, a well-defined thermodynamic property, of a ligand towards a (or multiple) targets. In fact, the fields of medicinal chemistry and drug design have made use of different variations of this theme over time depending on which type of information about binding was available in each case.

From an inductive point of view, already since the very early days of modern chemistry [3] structures of ligands and, hence, their binding properties, have been correlated to activities. Further milestones on this route were the establishment of quantitative structure-activity relationships and the comparison of ligands based on concepts of similarity or dissimilarity of shape and chemical properties. From a deductive point of view, the above theme summons medicinal chemists to look at biological activity from the perspective of processes and contributions that lead to binding, with structural information of the binding partners being of invaluable help.As such, the event of (reversible) binding is a consequence of association and dissociation processes and involves enthalpic and entropic components. If and how these separate processes and components can be modulated by modification of a ligand's structure for the sake of overall optimized binding properties is a “hot topic” at present in drug research. Furthermore, the deductive point of view allows one to apply a divide-and-conquer strategy when it comes to understanding and predicting binding from a theoretical perspective. As a first approximation, binding can be attributed to direct interactions between the binding partners mediated by an aqueous environment, to which contributions due to changes in the conformation and configuration of the binding partners add. While this approximation is valuable in that it allows optimizing the description of each of these terms separately, it also provokes the question to what extent does it hold or, phrased differently, when do cooperativity or compensation effects prevail over additivity?

The majority of topics for this book were selected following this deductive point of view, with an emphasis on rigorous approaches because I believe that these will be more successful in the long term than ad hoc ones. The selection also focused on topics that, at that time, had most quickened interests, had seen considerable progress, or had still been major stumbling blocks in the description and prediction of binding. Unsurprisingly, while much has been achieved in all of the covered areas as undoubtedly laid out in each of the chapters, not in all cases have methods or approaches lived up to one's expectations so far. I am grateful to the authors for pointing this out clearly – such insights will drive further developments that aim at improving our understanding of protein-ligand interactions. Finally, I also tried to balance topics related to biophysical experiments against theoretical and computational approaches, because I have learnt from my own work how well both sides can complement and enhance each other, and what joy this gives.

Last but not least, I express my gratitude to all contributors for providing insightful accounts on the topic of protein-ligand interactions, to the series editors Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers for giving me the opportunity to address this topic, to my current working group for providing fruitful comments about the chapters, and to Frank Weinreich and Heike Nöthe from the publisher Wiley-VCH for their continuous support, great help, and even greater patience.

Düsseldorf, Germany

Holger Gohlke

References

1. Venkatesan, K., Rual, J.F., Vazquez, A., Stelzl, U., Lemmens, I., Hirozane-Kishikawa, T., Hao, T., Zenkner, M., Xin, X.F., Goh, K.I., Yildirim, M.A., Simonis, N., Heinzmann, K., Gebreab, F., Sahalie, J.M., Cevik, S., Simon, C., de Smet, A.S., Dann, E., Smolyar, A., Vinayagam, A., Yu, H.Y., Szeto, D., Borick, H., Dricot, A., Klitgord, N., Murray, R.R., Lin, C., Lalowski, M., Timm, J., Rau, K., Boone, C., Braun, P., Cusick, M.E., Roth, F.P., Hill, D.E., Tavernier, J., Wanker, E.E., Barabasi, A.L. and Vidal, M., An empirical framework for binary interactome mapping. Nature Methods 2009. 6: 83–90.

2. Michal, G., Biochemical Pathways: Biochemie-Atlas. Spektrum Akademischer Verlag, Heidelberg: 1999.

3. Borman, S., New QSAR techniques eyed for environmental assessments. Chem Eng News 1990. 68: 20–23.

Part I

Binding Thermodynamics