Human Drug Targets E-Book

Edward D. Zanders

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 993

Veröffentlichungsjahr: 2015

Beschreibung

The identification of drug targets in a given disease has been central to pharmaceutical research from the latter half of the 20th century right up to the modern genomics era. Human Drug Targets provides an essential guide to one of the most important aspects of drug discovery - the identification of suitable protein and RNA targets prior to the creation of drug development candidates. The first part of the book consists of introductory chapters that provide the background to drug target discovery and highlight the way in which these targets have been organised into online databases. It also includes a user's guide to the list of entries that forms the bulk of the book. Since this is not designed to be a compendium of drugs, the emphasis will be on the known (or speculated) biological role of the targets and not on the issues associated with pharmaceutical development. The objective is to provide just enough information to be informative and prompt further searches, while keeping the amount of text for each of the many entries to a minimum. Human Drug Targets will prove invaluable to those drug discovery professionals, in both industry and academia, who need to make some sense of the bewildering array of online information sources on current and potential human drug targets. As well as creating order out of a complex target landscape, the book will act as an ideas generator for potentially novel targets that might form the basis of future discovery projects.

Leseprobe

Table of Contents

Cover

Title Page

Preface

Reference

Chapter 1: Introduction

1.1 Magic bullets

1.2 Background to modern pharmacology

1.3 Drug and therapeutic targets in the biomedical literature

1.4 How many drug targets are there?

1.5 Screening for active molecules

References

Chapter 2: Overview of the drug target compendium

2.1 Introductory comments

2.2 Selection of entries

2.3 Organization of entries

2.4 Summary of data entries

2.5 How to use this book

2.6 Final comments

References

Chapter 3: Cell surface and secreted proteins

3.1 G-protein-coupled receptors (GPCRs)

3.2 Nuclear hormone receptors (NHRS)

3.3 Cytokines and receptors

3.4 Adhesion molecules

3.5 Host defence molecules

3.6 Transporters and channels

References

Chapter 4: Enzymes: Part 1

4.1 Signalling enzymes

4.2 Protein modification

References

Chapter 5: Enzymes: Part 2

5.1 Lipids and related

5.2 Amino acids and related

5.3 Nucleotides and related

5.4 Carbohydrates and related

5.5 Vitamins, cofactors and related

5.6 DNA-processing enzymes

5.7 RNA-processing enzymes

5.8 Stress response and homeostasis

5.9 Miscellaneous enzymes

References

Chapter 6: Remaining annotated entries grouped by subcellular location

6.1 Cell surface and secreted proteins

6.2 Cytoskeleton

6.3 Cytoplasm to nucleus

6.4 Nucleus

6.5 Internal membranes and organelles

6.6 Cytoplasmic proteins

6.7 Subcellular location not annotated

Chapter 7: Non-coding RNAs

References

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Number of approved first-in-class or oncology drugs described in Refs [25] and [26] according to means of discovery

Chapter 02

Table 2.1 Data sources for drug and experimental compound entries

Table 2.2 Annotation categories of approximately 44% of the 19,123 protein-coding genes downloaded from the HGNC

Table 2.3 Example entries taken from Section 4.1.1 to illustrate the different types of annotation for target information

List of Illustrations

Chapter 01

Figure 1.1 Occurrence of the phrase ‘drug target’ and ‘therapeutic target’ in papers published between 1979 and 2014.

Figure 1.2 FDA approvals by therapeutic area.

Chapter 02

Figure 2.1 Distribution of reference annotations by year of publication. Numbers taken from PubMed website after loading PMID identifiers from Chapters 3–7

Figure 2.2 Data collection and organization schema. Gene names and symbols using the HGNC nomenclature were used as entries for a compendium of drug targets. Data on drugs and diseases, and references to target potential, were fed into the gene list to create a group of annotated entries. All gene entries, whether annotated or not, were sorted into categories and headings within chapters using data from UniProt, GO, etc. as indicated

Figure 2.3 HGNC symbol report page accessed from http://www.genenames.org for MAP2K2 showing the synonym MEK2 and other information

Guide

Cover

Table of Contents

Begin Reading

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Human Drug Targets

A Compendium for Pharmaceutical Discovery

Edward D. Zanders

PharmaGuide Ltd, Cambridge, UK

This edition first published 2016© 2016 John Wiley & Sons, Ltd.

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ISBN: 9781118849859

A catalogue record for this book is available from the British Library.

Preface

The drug discovery scientist in the 21st century has access to a vast amount of information about the workings of living organisms and the nature of human disease. It is now possible to survey the entire human genome and proteome in a systematic way at different levels of organization (through sequence and expression analysis, epigenetic modification, etc.) in order to identify potential targets for drug development. This information comes from a rapidly expanding global scientific workforce that is producing an equally expanding output of literature, aided in part by the open-access publishing model.

My personal involvement in drug target selection started in a large pharmaceutical company, looking at molecules of the human immune system that could be useful as targets for drugs to treat allergic and autoimmune diseases. This was the time when cytokine biology was beginning to develop with the discovery of the first interleukins; there was a compelling case for making inhibitors of cytokine–receptor interactions that would interfere with immunoinflammatory processes in a highly selective manner. At the time, there was a humble tally of just three named interleukins (the latest at the time of writing is interleukin-37). The search for drug targets, then as now, involved a survey of the basic biomedical literature: the latest issue of Nature (or similar), delivered by post (in pre-Internet days), might contain the description of a new cytokine or adhesion molecule or something that was shown to affect the behaviour of cells, at least in vitro.

The landscape of target discovery changed around the turn of the millennium with the rise of genomics. The increasing availability of human genome sequence (some of it still only accessible by subscription) meant that target discovery could potentially become less hit and miss. It was much easier to identify closely related protein families using sequence analysis; families with established drug targets like the peptidases could be mined for target opportunities, a process that continues to this day.

From a pharmaceutical perspective, the ultimate aim of a systematic survey of the human genome must be the delineation of all possible drug targets. I (and many others) have often wondered how big this number is; it was while reading one of the several reviews on this subject that the idea of a compendium of drug targets came to me. The Oxford English Dictionary definition puts the idea into words perfectly: ‘(a compendium is) a collection of concise but detailed information about a particular subject, especially in a book or other publication’. Furthermore, the word is derived from the Latin compendere, ‘what is weighed together’, literally meaning ‘profit, saving’, something with a certain commercial appeal. This book then is a compendium of human drug targets, both established and potential, based on the roughly 19,000 protein-coding genes of the human genome plus some non-coding RNA targets. Since only human genes are covered, this excludes most infectious disease targets except those relating to host cell–pathogen interactions. The compendium is concise, in having just enough information to attract the readers’ attention to a particular entry, then allowing them to access the relevant information online using the HUGO Gene Nomenclature Committee (HGNC) approved gene names and symbols. The book format presents the information in such a way as to encourage browsing by thumbing through pages rather than by scrolling down a screen and getting distracted by various hyperlinks.

There is sufficient information on potential targets to keep investigators busy for a long time. The book contains a survey of approximately 50% of the human protein-coding genome and includes established drug target classes such as enzymes, receptors and transporters. The remaining gene entries will be curated for inclusion in a future volume, eventually resulting in a significant coverage of the human genome. It is inevitable that more data will become available for each entry as the years go by, but so long as there is a fixed point of reference in the book, changes in nomenclature will be flagged online in the HGNC pages and new publications revealed through the ‘related citations’ feature in PubMed.

There is clearly no shortage of potential drug targets, but of course not all are created equal. Going back to my earlier days with cytokines, we discovered the hard way that the small-molecule receptors so successfully targeted by the medicinal chemists and pharmacologists are not the same as cytokine receptors because the latter generally lack suitable pockets for high-affinity binding of small molecules. This did not in any way deter us (or indeed our rivals) as we tried to find small-molecule inhibitors by random screening. To paraphrase the 18th-century English writer Samuel Johnson, it was ‘the triumph of hope over experience’ (although he was referring to second marriages). It takes a vast amount of effort to move from drug targets to effective medicines. Sometimes, it takes a complete re-engineering of drug development, as happened with the introduction of monoclonal antibodies or other recombinant proteins as cytokine inhibitors. Thus, many years later, after a fruitless search for small-molecule inhibitors of interleukin action for atopic and asthmatic diseases (IL-4 and IL-5), positive clinical data with antibodies are finally becoming available. Hopefully, it will not be too long before the same level of technological maturity can be achieved with RNA drugs and gene editing/therapy.

Every effort has been made to minimize errors and omissions in content and layout. If the book is likened to a large menu, for example, some desserts will appear under ‘entrées’ and so on. However, I like to think that I have been reasonably conscientious; perhaps my DNA contains a relevant mutation in KATNAL2, a gene that might show some association with this personality trait [1].

Finally, I would like to thank the organizations that have made it possible to select gene entries and annotations for this compendium. These include the HGNC and UniProt Knowledgebase, both based at the European Bioinformatics Institute in Cambridge, United Kingdom, and the US National Library of Medicine for PubMed references. In particular, I’d like to thank Dr Elspeth Bruford at the HGNC for her helpful comments as well as permission to show the HGNC web page in Chapter 2.

I am grateful to Wiley, in particular Lucy Sayer for her willingness to accept this book project and Celia Carden for helping to turn it into reality. Their enthusiasm is much appreciated.

Last, but not least, I thank my wife Rosie for her patience while I spent many hours in front of the computer sorting through lists; I dedicate this book to her and to our children.

Reference

1. De Moor MHM

et al

. (2012) Meta-analysis of genome-wide association studies for personality.

Molecular Psychiatry

17

, 337–49.

Chapter 1Introduction

Global sales of prescription medicines reached nearly 1 trillion dollars in 2013 and show no sign of abating [1]. At first sight, this might give the impression that all is well with the biopharmaceutical industry; however, this hides the well-documented fact that company pipelines of innovative drugs are not full enough to keep up with the escalating costs and difficulty of bringing them to market [2]. There are many points in the drug development pipeline where improvements can be made to increase the chance of success. One such point lies at the beginning of the discovery process itself, the identification of drug targets with therapeutic potential. Organized drug target discovery was once almost exclusively undertaken in the pharmaceutical industry, but this situation is changing through stronger collaboration between companies and academia. Regardless of where drug target discovery is actually undertaken, there is a need for as much scientific information as possible to guide the research; this information is provided through biology, chemistry and medicine but is overwhelming in its totality. Individual pieces of information can be readily accessed in online databases, publications and verbal communication with colleagues, but it is difficult to present this totality of target opportunities in a format that is easily browsed. This book is designed to address this issue by presenting a large list of potential human drug targets in a physical form that is easy to browse through, rather like a catalogue; each entry contains just enough information to attract interest without adding undue clutter to the text while at the same time supplying the key information required to follow up online. This is a book about potential and actual human drug targets, not the drugs themselves; microbial targets are not included in order to keep the book within manageable proportions for the sake of both the reader and the author.

This chapter sets the scene for the rest of the book by describing the drug target concept from its origins in 19th century pharmacology through to the Human Genome Project and the present day.

1.1 Magic bullets

If we picture an organism as infected by a certain species of bacterium, it will obviously be easy to effect a cure if substances have been discovered which have an exclusive affinity for these bacteria and act deleteriously or lethally on these alone, while at the same time they possess no affinity for the normal constituents of the body and can therefore have the least harmful, or other, effect on that body. Such substances would then be able to exert their full action exclusively on the parasite harboured within the organism and would represent, so to speak, magic bullets, which seek their target of their own accord.

These words were spoken in 1906 by Paul Ehrlich as part of an address to inaugurate the Georg-Speyer Haus, an institute devoted to chemotherapy research in Frankfurt, Germany [3]. His comments provide a useful summary of the concept of a drug target and are applicable to all diseases, not just those caused by infectious agents. Ehrlich’s research represented a transition point between the beginnings of the modern pharmacology that emerged in the 19th century and the description and eventual isolation of defined receptors for synthetic drug molecules that occurred in the 20th.

The following sections present modern ideas about drug targets in a historical context, highlighting the relatively recent molecular characterization of receptors for drugs which, in many cases, have been used for over a century.