Scaffold Hopping in Medicinal Chemistry E-Book

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

Seitenzahl: 532

Veröffentlichungsjahr: 2013

Beschreibung

This first systematic treatment of the concept and practice of scaffold hopping shows the tricks of the trade and provides invaluable guidance for the reader's own projects.

The first section serves as an introduction to the topic by describing the concept of scaffolds, their discovery, diversity and representation, and their importance for finding new chemical entities. The following part describes the most common tools and methods for scaffold hopping, whether topological, shape-based or structure-based. Methods such as CATS, Feature Trees, Feature Point Pharmacophores (FEPOPS), and SkelGen are discussed among many others. The final part contains three fully documented real-world examples of successful drug development projects by scaffold hopping that illustrate the benefits of the approach for medicinal chemistry.

While most of the case studies are taken from medicinal chemistry, chemical and structural biologists will also benefit greatly from the insights presented here.

Leseprobe

Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Part One: Scaffolds: Identification, Representation Diversity, and Navigation

Chapter 1: Identifying and Representing Scaffolds

1.1 Introduction

1.2 History of Scaffold Representations

1.3 Functional versus Structural Molecular Scaffolds

1.4 Objective and Invariant Scaffold Representations

1.5 Maximum Common Substructures

1.6 Privileged Scaffolds

1.7 Conclusions

Acknowledgments

References

Chapter 2: Markush Structures and Chemical Patents

2.1 Introduction

2.2 Encoding Markush Structures

2.3 The Search Algorithm

2.4 Using Periscope for Scaffold Hopping

2.5 Conclusions

References

Chapter 3: Scaffold Diversity in Medicinal Chemistry Space

3.1 Introduction

3.2 Scaffold Composition of Medicinal Chemistry Space

3.3 Metrics for Quantifying the Scaffold Diversity of Medicinal Chemistry Space

3.4 Visualizing the Scaffold Diversity of Medicinal Chemistry Space

3.5 Conclusions

References

Chapter 4: Scaffold Mining of Publicly Available Compound Data

4.1 Introduction

4.2 Scaffold Definition

4.3 Selectivity of Scaffolds

4.4 Target Promiscuity of Scaffolds

4.5 Activity Cliff-Forming Scaffolds

4.6 Scaffolds with Defined Activity Progression

4.7 Scaffold Diversity of Pharmaceutical Targets

4.8 Conclusions

References

Chapter 5: Exploring Virtual Scaffold Spaces

5.1 Introduction

5.2 The Comprehensive Enumeration of Parts of Chemical Space

5.3 The Iterative Generation of Virtual Compounds

5.4 Virtual Synthesis

5.5 Visualizations of Scaffold Space

5.6 A Perspective on the Past and the Future

References

Part Two: Scaffold-Hopping Methods

Chapter 6: Similarity-Based Scaffold Hopping Using 2D Fingerprints

6.1 Fingerprints

6.2 Retrospective Studies of Scaffold Hopping Using 2D Fingerprints

6.3 Predictive Studies of Scaffold Hopping Using 2D Fingerprints

6.4 Conclusions

References

Chapter 7: CATS for Scaffold Hopping in Medicinal Chemistry

7.1 Chemically Advanced Template Search

7.2 Retrospective Evaluation of Enrichment and Scaffold Hopping Potential

7.3 Prospective Scaffold-Hopping Applications

7.4 Conclusions

References

Chapter 8: Reduced Graphs

8.1 Introduction

8.2 Generating Reduced Graphs

8.3 Comparison and Usage of Reduced Graphs

8.4 Summary

References

Chapter 9: Feature Trees

9.1 Introduction

9.2 Feature Tree Generation

9.3 Feature Tree Comparison

9.4 Retrospective Validation

9.5 Implementations and Applications

9.6 Conclusions

Acknowledgment

References

Chapter 10: Feature Point Pharmacophores (FEPOPS)

10.1 Similarity Searching in Drug Discovery

10.2 FEPOPS: An Analogy to Image Compression

10.3 Computing FEPOPS

10.4 Scaling and Correlations

10.5 Defining Scaffold Hopping

10.6 FEPOPS in Similarity Searching and Scaffold Hopping

10.7 Alternative Alignment

10.8 In Silico Target Prediction

10.9 Chemical Space Uniqueness

10.10 Perspective on FEPOPS' 10 Year Anniversary

References

Chapter 11: Three-Dimensional Scaffold Replacement Methods

11.1 Introduction

11.2 Generic Three-Dimensional Scaffold Replacement Workflow

11.3 SHOP: Scaffold HOPping by GRID-Based Similarity Searches

11.4 ReCore

11.5 BROOD

11.6 Conclusions

Acknowledgment

References

Chapter 12: Spherical Harmonic Molecular Surfaces (ParaSurf and ParaFit)

12.1 Introduction

12.2 Spherical Harmonic Surfaces

12.3 Rotating Spherical Polar Fourier Expansions

12.4 Spherical Harmonic Surface Shape Similarity

12.5 Calculating Consensus Shapes and Center Molecules

12.6 The ParaSurf and ParaFit Programs

12.7 Using Consensus Shapes to Probe the CCR5 Extracellular Pocket

12.8 Conclusions

References

Chapter 13: The XED Force Field and Spark

13.1 Pharmacological Similarity – More than Just Chemical Structure

13.2 Improving the Generation of Valid Molecular Fields

13.3 The eXtended Electron Distribution (XED) Force Field

13.4 The XED Force Field Applied to Scaffold Hopping in Spark

13.5 How Spark Works

13.6 Application of Spark in Drug Discovery Scenarios

13.7 P38 Kinase Inhibitor Fragment Growing Using Spark

13.8 Creating New Molecules

13.9 New Potential Inhibitors

13.10 The Far-Reaching Consequences of Using Molecular Fields as Measures of Similarity

Acknowledgments

References

Chapter 14: Molecular Interaction Fingerprints

14.1 Introduction

14.2 Target-Annotated Ligand Fingerprints

14.3 Ligand-Annotated Target Fingerprints

14.4 True Target–Ligand Fingerprints

14.5 Conclusions

References

Chapter 15: SkelGen

15.1 Introduction

15.2 Structure Generation and Optimization

15.3 Validation Studies

15.4 Scaffold Hopping Using Fixed Fragments

15.5 Scaffold Hopping Using Site Points

15.6 Further Considerations for Scaffold Hopping

15.7 Conclusion

Acknowledgments

References

Part Three: Case Studies

Chapter 16: Case Study 1: Scaffold Hopping for T-Type Calcium Channel and Glycine Transporter Type 1 Inhibitors

16.1 Introduction

16.2 T-Type Calcium Channel Inhibitors

16.3 Scaffold Hopping to Access Novel Calcium T-Type Channel Inhibitors

16.4 Scaffold Hopping to Access Novel Glycine Transporter Type 1 (GlyT1) Inhibitors

16.5 Conclusions

References

Chapter 17: Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

17.1 Introduction

17.2 Neurokinin 1 (NK1) Therapeutic Areas

17.3 The Neurokinin 1 Receptor (NK1R) and Its Mechanism

17.4 Neurokinin 1 Antagonists

17.5 NK1 Receptor: Target Active Site and Binding Mode

17.6 Bioisosteric Replacements in NK1 Receptor Antagonist

17.7 Bioisosteric Replacements in NK1 Receptor Antagonist: A Retrospective Study

17.8 Summary and Conclusions

References

Chapter 18: Case Study 3: Fragment Hopping to Design Highly Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors

18.1 Fragment-Based Drug Design

18.2 Minimal Pharmacophoric Elements and Fragment Hopping

18.3 Fragment Hopping to Design Novel Inhibitors for Neuronal Nitric Oxide Synthase

18.4 Fragment Hopping to Optimize Neuronal Nitric Oxide Synthase Inhibitors

18.5 Application of Neuronal Nitric Oxide Synthase Inhibitors to the Prevention of Cerebral Palsy

Acknowledgment

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:

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Data Mining in Drug Discovery

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List of Contributors

Jürgen Bajorath

Rheinische Friedrich-Wilhelms-Universität

Department of Life Science Informatics, B-IT

LIMES Program Unit Chemical Biology and Medicinal Chemistry

Dahlmannstr. 2

53113 Bonn

Germany

Kristian Birchall

MRC Technology

Centre for Therapeutics Discovery

1-3 Burtonhole Lane

London NW7 1AD

UK

Julian Blagg

The Institute of Cancer Research

Division of Cancer Therapeutics

Cancer Research UK Cancer Therapeutics Unit

15 Cotswold Road

Sutton, Surrey SM2 5NG

UK

Nathan Brown

The Institute of Cancer Research

Division of Cancer Therapeutics

Cancer Research UK Cancer Therapeutics Unit

15 Cotswold Road

Sutton, Surrey SM2 5NG

UK

David Anthony Cosgrove

AstraZeneca

Discovery Sciences

Chemistry Innovation Centre

Mereside 30S391

Alderley Park

Macclesfield SK10 4TG

UK

Jérémy Desaphy

UMR 7200 CNRS/Université de Strasbourg

Laboratoire d'Innovation Thérapeutique

MEDALIS Drug Discovery Center

74 route de Rhin

Illkirch 67400

France

Ye Hu

Rheinische Friedrich-Wilhelms-Universität

Department of Life Science Informatics, B-IT

LIMES Program Unit Chemical Biology and Medicinal Chemistry

Dahlmannstr. 2

53113 Bonn

Germany

Jeremy L. Jenkins

Novartis Institutes for BioMedical Research

Developmental and Molecular Pathways

220 Massachusetts Avenue

Cambridge, MA 02139

USA

Haitao Ji

University of Utah

Department of Chemistry

Center for Cell and Genome Science

315 South 1400 East

Salt Lake City, UT 84112-0850

USA

Christian P. Koch

Eidgenössische Technische Hochschule (ETH)

Department of Chemistry and Applied Biosciences

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Leah C. Konkol

Vanderbilt University Medical Center

Department of Chemistry

2213, Garland Avenue

Nashville, TN 37232-6600

USA

Boris Kroeplien

UCB Celltech

208 Bath Road

Slough SL1 3WE

UK

Sarah R. Langdon

The Institute of Cancer Research

Division of Cancer Therapeutics

Cancer Research UK Cancer Therapeutics Unit

15 Cotswold Road

Sutton, Surrey SM2 5NG

UK

Craig W. Lindsley

Vanderbilt University Medical Center

Department of Chemistry

2213, Garland Avenue

Nashville, TN 37232-6600

USA

Violeta I. Pérez-Nueno

Harmonic Pharma

615 Rue du Jardin Botanique

54600 Villers-lès-Nancy

France

Francesca Perruccio

Francesca Perruccio

Novartis Pharma AG

Postfach

CH-4002 Basel

Switzerland

William R. Pitt

University of Cambridge

Department of Biochemistry

80 Tennis Court Road

Cambridge CB2 1GA

UK

Michael Reutlinger

Eidgenössische Technische Hochschule (ETH)

Department of Chemistry and Applied Biosciences

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

David W. Ritchie

Inria Nancy – Grand Est

Team Orpailleur

615 Rue du Jardin Botanique

54600 Villers-lès-Nancy

France

Didier Rognan

UMR 7200 CNRS/Université de Strasbourg

Laboratoire d'Innovation Thérapeutique

MEDALIS Drug Discovery Center

74 route de Rhin

Illkirch 67400

France

Gisbert Schneider

Eidgenössische Technische Hochschule (ETH)

Department of Chemistry and Applied Biosciences

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Petra Schneider

Eidgenössische Technische Hochschule (ETH)

Department of Chemistry and Applied Biosciences

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Timothy J. Senter

Vanderbilt University Medical Center

Department of Chemistry

2213, Garland Avenue

Nashville, TN 37232-6600

USA

Richard B. Silverman

Northwestern University

Department of Chemistry

Chemistry of Life Processes Institute

Center for Molecular Innovation and Drug Discovery

2145 Sheridan Road

Evanston, IL 60208-3113

Martin Slater

New Cambridge House

Bassingbourn Road

Litlington

Cambridgeshire

SG8 0SS

UK

Nickolay Todoroff

Eidgenössische Technische Hochschule (ETH)

Department of Chemistry and Applied Biosciences

Institute of Pharmaceutical Sciences

Wolfgang-Pauli-Str. 10

8093 Zürich

Switzerland

Nikolay P. Todorov

Molscape Research Limited

145–157 St John Street

London EC1V 4PW

UK

Andy Vinter

New Cambridge House

Bassingbourn Road

Litlington

Cambridgeshire SG8 0SS

UK

Peter Willett

University of Sheffield

Information School

211 Portobello Street

Sheffield S1 4DP

UK

Preface

In 1999, Gisbert Schneider coined the term “scaffold hopping” for a systematic approach to modify the molecular skeleton of a lead structure [1]. Whereas in bioisosteric replacement atoms or small groups are substituted by other ones with identical or at least similar stereoelectronic features [2], scaffold hopping exchanges the central part of a molecule by a molecular frame of similar shape and pharmacophoric pattern [3]. Correspondingly, scaffold hopping may be considered as an extension of bioisosteric replacement. In this manner, it provides a conceptual and practical route for generating new chemistry and lead series with higher efficacy, better or modified selectivity, and/or improved pharmacokinetic properties, based on known active principles.

As often in science, this approach is also not completely new. The modification or exchange of a molecular scaffold was already applied in the chemical variation of morphine, quinine, some steroid hormones (e.g., estradiol), and β-blockers, to list only a few examples. Looking at naturally occurring β-lactams, that is, the penicillins, cephalosporins, and monobactams, we see that also nature sometimes uses this principle. Like in “fragment-based design,” where a breakthrough came only after the description of the advantages of this method, the definition “scaffold hopping” appealed medicinal chemists to use this strategy – and fueled its systematic application in lead structure search and optimization. Marketed analogs of celecoxib (Celebrex®), sildenafil (Viagra®), and several kinase inhibitors are recent examples of drugs and clinical candidates resulting from this approach.

The volume is logically organized in three parts. An introductory part deals with the representation, diversity, and navigation aspects of scaffold hopping. The next section is dedicated to topological methods, feature trees, shape-based methods, three-dimensional scaffold replacement methods as well as pharmacophore- and structure-based methods of scaffold hopping. Finally, some case studies demonstrate the value of scaffold hopping in all important target classes, exemplified by the design of ligands of the T-type calcium channel, the glycin transporter type 1, the neurokinin 1 receptor, and nitric oxide synthase.

The series editors highly appreciate that after editing the first monograph Bioisosteres in Medicinal Chemistry, Nathan Brown also undertook the effort to edit this monograph. We are very grateful that he organized this work, cooperating with so many excellent authors. Surely this book adds another fascinating new facet to our book series on “Methods and Principles in Medicinal Chemistry.” Last but not least, we thank Wiley-VCH, in particular Frank Weinreich and Heike Nöthe, for their valuable contributions to this project and the entire series.

DüsseldorfWeisenheim am SandZurichJuly 2013Raimund MannholdHugo KubinyiGerd Folkers

References

1. Schneider, G., Neidhart, W., Giller, T., and Schmid, G. (1999) “Scaffold-hopping” by topological pharmacophore search: a contribution to virtual screening. Angewandte Chemie, International Edition, 38, 2894–2896.

2. Brown, N. (ed.) (2012) Bioisosteres in Medicinal Chemistry, vol. 54, Methods and Principles in Medicinal Chemistry (eds R. Mannhold, H. Kubinyi, and G. Folkers), Wiley-VCH Verlag GmbH, Weinheim.

3. Sun, H., Tawa, G., and Wallquist, A. (2012) Classification of scaffold-hopping approaches. Drug Discovery Today, 17, 310–324.

A Personal Foreword

“…I want to stand as close to the edge as I can without going over. Out on the edge you see all the kinds of things you can't see from the center.”

Player Piano (1952)Kurt Vonnegut, Jr.

The foundation of a medicinal chemistry project is the determination and selection of the molecular scaffolds from which the potential drugs are grown. Therefore, it is essential that this fundamental core element be selected appropriately and with careful consideration. The selection of scaffolds and identification of ideal replacement scaffolds can be greatly assisted by computational analyses.

This book is the first to be dedicated to the analysis of molecular scaffolds in drug discovery and the discussion of the plethora of computational approaches that have been reported in scaffold hopping. Scaffold hopping is a subset of bioisosteric replacement where one tries to replace the core motif of a molecule while retaining important interaction potential, whether functionally or literally the necessary scaffolding for decorating with functional substituents.

There has been much published on what constitutes a molecular scaffold over the last century since the advent of Markush structures. A medicinal chemist tends to know it when they see it, whereas computational scientists apply various algorithms to identify what may be the scaffold of a chemical series or individual molecules. Part One of this book covers fully the many considerations in molecular scaffold identification, representation, diversity, and navigation. These are essential definitions and analyses that are prerequisites for application in scaffold hopping campaigns.

Part Two of this book, and the most substantial, covers a well-established subset of the many different computational methods that have been developed and applied in recent years. These range from ligand-based topological pharmacophores to abstracting three-dimensional structures in a variety of ways, including the use of protein structures.

Finally, and of key importance to the presentation of any approach, the book concludes with three chapters in Part Three in which scaffold hopping techniques and approaches have been applied prospectively in real projects. These case studies consider scaffold hopping applied to designing ligands in four targets: nitric oxide synthase, the neurokinin 1 receptor, the T-type calcium channel, and the glycine transporter type 1.

I would like to extend my personal thanks to the contributors of all of the chapters in this book who have devoted so much time and effort in producing work that is of the high standard that we have come to expect in this book series “Methods and Principles in Medicinal Chemistry.” I would like to thank the series editors Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers for commissioning to edit this book and also the previous book Bioisosteres in Medicinal Chemistry. Finally, I would like to thank the Wiley-VCH team for helping me pull this book together and making my life as editor a lot simpler in many ways; in particular, I would like to thank Frank Weinreich and Heike Nöthe for their invaluable efforts.

This book has been a labor of love for me and I am delighted that this book has formed so well through the duration of this project. I can only hope that you as the reader get as much out of reading it as I did in editing.

London, 2013Nathan Brown

Part One

Scaffolds: Identification, Representation Diversity, and Navigation

1

Identifying and Representing Scaffolds

Nathan Brown

1.1 Introduction

Drug discovery and design is an inherently multiobjective optimization process. Many different properties require optimization to develop a drug that satisfies the key objectives of safety and efficacy. Scaffolds and scaffold hopping, the subject of this book, are an attempt to identify appropriate molecular scaffolds to replace those that have already been identified [1,2]. Scaffold hopping has also been referred to as lead hopping, leapfrogging, chemotype switching, and scaffold searching in the literature [3–6]. Scaffold hopping is an approach to modulating important properties that may contravene what makes a successful drug: safety and efficacy. Therefore, due consideration of alternative scaffolds should be considered throughout a drug discovery program, but it is perhaps more easily explored earlier in the process. Scaffold hopping is a subset of bioisosteric replacement that focuses explicitly on identifying and replacing appropriate central cores that function similarly in some properties while optimizing other properties. While bioisosteric replacement is not considered to a significant degree in this book, a sister volume has recently been published [7], many of the approaches discussed in this book are also applicable to bioisosteric replacement.

Some properties that can be modulated by judicious replacement of scaffolds are binding affinity, lipophilicity, polarity, toxicity, and issues around intellectual property rights. Binding affinity can sometimes be improved by introducing a more rigid scaffold. This is due to the conformation being preorganized for favorable interactions. One example of this was shown recently in a stearoyl-CoA desaturase inhibitor [8]. An increase in lipophilicity can lead to an increase in cellular permeability. The replacement of a benzimidazole scaffold with the more lipophilic indole moiety was recently presented as a scaffold replacement in an inhibitor targeting N5SB polymerase for the treatment against the hepatitis C virus [9]. Conversely, replacing a more lipophilic core with the one that is more polar can improve the solubility of a compound. The same two scaffolds as before were used, but this time the objective was to improve solubililty, so the indole was replaced for the benzimidazole [10]. Sometimes, the central core of a lead molecule can have pathological conditions in toxicity that needs to be addressed to decrease the chances of attrition in drug development. One COX-2 inhibitor series consisted of a central scaffold of diarylimidazothiazole, which can be metabolized to thiophene S-oxide leading to toxic effects. However, this scaffold can be replaced with diarylthiazolotriazole to mitigate such concerns [11,12]. Finally, although not a property of the molecules under consideration , it is often important to move away from an identified scaffold that exhibits favorable properties due to the scaffold having already been patented. The definition of Markush structures will be discussed later in this chapter and more extensively in Chapter 2.