Novel Targets in Drug Discovery

Publication Date	April 2004
Publisher	Scrip Reports
Product Type	Report
Pages	78
ISBN Number	not applicable
Product Code	SCR00006

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Summary

In recent years, the process of drug discovery has changed immeasurably. It has gone from a process that was largely disease-focused to one that is target-led. This change has been driven by a number of factors, among them technological advances and economic pressures.

Under the old paradigm, drug discovery began with the identification of a human disease and the development of an animal model of it. Chemical compounds that ameliorated the animal disease were then used as the starting point for the development of a new therapeutic substance. The present approach focuses very much on the identification of potential drug targets, which are typically individual genes or gene products. If the gene underlying a particular disease can be identified, the reasoning goes, then the discovery of chemical compounds or biological agents that modulate the targets, and therefore hopefully treat the disease, can be automated, which is vastly more efficient than dealing with animal models.

However, not everyone agrees that this genetic reductionist approach is valid. While it appears superficially attractive, a number of objections, both theoretical and practical, have been raised. Nevertheless, it has been widely embraced by the pharmaceutical industry.

This report provides an overview of the concept of drug targets, and discusses their place in modern drug discovery. It looks at the role of technologies such as genomics, proteomics and bioinformatics in target identification, as well as describing the downstream processes such as target validation, lead discovery, lead optimisation and clinical development. It also discusses the various types of drug targets using specific examples where appropriate.

Chapter 1 provides a historical perspective to drug discovery, looking briefly at the pioneering work of researchers such as Ehrlich, Domagk, Fleming, Ahlquist and others. Using specific examples, it discusses the development of receptor theory, describes the role of second messengers in mediating the effects of drugs, and shows how the concept of drug receptors was gradually overtaken by an appreciation of targets in the wider sense.

Chapter 2 discusses the changes in drug discovery techniques that came about during the closing years of the 20th century. Advances in genetics, particularly functional genomics and the Human Genome Project have revolutionised the way that drugs are discovered, and these techniques are discussed in that context. Chapter 2 also looks at the processes of target validation, lead discovery and optimisation, preclinical development and clinical development.

Chapter 3 focuses on drug discovery in the post-genomic era. It describes benefits that genomic and post-genomic sciences promise to bring to the process of drug discovery, and discusses some of the criticisms levelled against the genetic reductionist approach to drug discovery. The Human Genome Project revealed far fewer genes in the human genome than had been supposed, and Chapter 3 assesses the implications of this for drug discovery, asking just how many potential targets there are concealed within the human genome.

Chapter 4 looks specifically at the major types of drug target: DNA, nuclear receptors, enzymes, ion channels, receptors, and hormones and factors. In each category, the report provides a classification of drug targets, describes some of the techniques used to study them, and gives examples of current R&D in that particular area.

Finally, a series of appendices provides case-studies illustrating the use of genomics data in the identification of drug targets and how an enzyme target might be used in drug discovery.

Content

Chapter 1 Historical Perspective
Chapter 2 Drug Discovery In The Late Twentieth Century
- 2.1 The basis of inheritance
- 2.2 The genetic code
- 2.3 Biotechnology
- 2.4 The Human Genome Project
- 2.4.1 Celera enters the race
- 2.4.2 The major findings
- 2.4.3 Implications for drug discovery
- 2.5 Functional genomics
- 2.5.1 Knockouts
- 2.5.2 Antisense
- 2.5.3 RNA interference
- 2.5.4 Transgenics
- 2.5.5 Limitations of gene-modified animal models
- 2.5.6 DNA microarrays
- 2.6 Target identification
- 2.7 Target validation
- 2.8 Lead discovery
- 2.9 Lead optimisation
- 2.10 Proteomics
- 2.11 Preclinical development
- 2.12 Clinical development
Chapter 3 Drug Discovery In The Post-Genomic Era
- 3.1 'Traditional' drug discovery
- 3.2 The promise of genomics
- 3.2.1 Genomics and drug discovery
- 3.2.2 Unresolved issues
- 3.3 Reductionism criticised
- 3.4 Target identification
- 3.5 Discovery screens
- 3.6 How many targets?
- 3.6.1 The druggable genome
- 3.6.2 Implications for drug discovery
- 3.7 The importance of druggability
- 3.7.1 The impact of HTS
- 3.7.2 Predicting druggability
- 3.7.3 Other approaches
- 3.7.4 Artificial intelligence
Chapter 4 The Nature Of Drug Targets
- 4.1 DNA
  - 4.1.1 Techniques for studying DNA interactions
  - 4.1.2 Drugs in development that target DNA
- 4.2 Nuclear receptors
  - 4.2.1 Oestrogen receptors
  - 4.2.2 Retinoid receptors
  - 4.2.3 Vitamin D receptors
  - 4.2.4 Glucocorticoid receptors
  - 4.2.5 Thyroid hormone receptors
  - 4.2.6 Peroxisome proliferator-activated receptors
  - 4.2.7 Liver X receptors
  - 4.2.8 Techniques for studying nuclear receptors
  - 4.2.9 Current research into drugs that target nuclear receptors
- 4.3 Enzymes
  - 4.3.1 Enzyme inhibitors
  - 4.3.2 Techniques used to study enzyme activity
- 4.4 Ion channels
  - 4.4.1 How ion channels are studied
  - 4.4.2 Other techniques for studying ion channels
  - 4.4.3 Recent developments
- 4.5 Receptors
  - 4.5.1 G proteins
  - 4.5.2 Tyrosine kinase receptors
  - 4.5.3 Receptor families
    - Muscarinic acetylcholine receptors
    - Adenosine receptors
    - Adrenergic receptors
    - Angiotensin receptors
    - Cannabinoid receptors
    - Chemokine receptors
    - Cholecystokinin receptors
    - Dopamine receptors
    - Endothelin receptors
    - ?-aminobutyric acid (GABA) receptors
    - Metabotropic glutamate receptors
    - Glucagon receptors
    - Histamine receptors
    - 5-hydroxytryptamine receptors
    - Leukotriene receptors
    - Melanocortin receptors
    - Melatonin receptors
    - Neuropeptide Y receptors
    - P2Y receptors
    - Opioid receptors
    - Prostanoid receptors
    - Somatostatin receptors
    - Urotensin receptors
    - VIP and PACAP receptors
- 4.6 Hormones and factors
Chapter 5 Conclusions
Appendix I A Prototypic Genomics-Derived Drug Discovery Target
Appendix II Drug Discovery Based On An Enzyme As The Target
Appendix III Recommended Further Reading
References
List Of Tables
- Table 1.1 Examples of ligands using various second messenger systems
- Table 2.1 Composition of nucleic acids
- Table 2.2 What sequencing the human genome does not reveal
- Table 3.1 Blockbusters whose success was not anticipated at the time of target
- selection
- Table 3.2 The biochemical classes of therapeutic drug targets
- Table 3.3 Number of potential drug targets
- Table 4.1 Typical concentrations of ions inside and outside the cell.
- Table 4.2 Pharmaceutical research involving dopamine receptors
- Table 4.3 Classification of 5-HT receptors
- Table 4.4 Hormones and factors used as drug targets
List Of Figures
- Figure 1.1 Traditional routes of new drug discovery
- Figure 1.2 cAMP as a second messenger
- Figure 2.1 Gene expression
- Figure 2.2 The central dogma of biology
- Figure 2.3 The drug discovery process
- Figure 4.1 Alkylation of guanine residue in DNA by nitrogen mustard.
- Figure 4.2 Structure of metronidazole
- Figure 4.3 Diagrammatic representation of the patch-clamp technique
- Figure 4.4 Single well model of Essen IonWorks system
Abbreviations
- 5-HT 5-hydroxytryptamine
- 7TM seven transmembrane (receptor)
- ACD Available Chemicals Database
- ACE angiotensin converting enzyme
- ACTH adrenocorticotropic hormone
- ADEPT antibody-directed enzyme prodrug therapy
- ANF atrial natriuretic factor
- ATP adenosine triphosphate
- cAMP cyclic adenosine monophosphate
- cGMP cyclic guanosine monophosphate
- CMC Comprehensive Medicinal Chemistry
- CNS central nervous system
- COX-2 cyclo-oxygenase
- DNA deoxyribonucleic acid
- DoE (US) Department of Energy
- dsRNA double-stranded RNA
- DVD digital versatile disc
- EORTC European Organisation for Research and Treatment of Cancer
- FLIPR fluorescent imaging plate reader
- FRET fluorescence resonance energy transfer
- FSH follicle-stimulating hormone
- GABA ?-aminobutyric acid
- GDEPT gene-directed enzyme prodrug therapy
- GDP guanosine diphosphate
- GnRH gonadotropin releasing hormone
- GPCR GTP-binding protein-coupled receptor
- GTP guanosine triphosphate
- HGP Human Genome Project
- HIV human immunodeficiency virus
- hnRNA heterogeneous nuclear RNA
- HPLC high-performance liquid chromatography
- HTS high-throughput screening
- IGF insulin-like growth factor
- INN International Nonproprietary Name
- IUPHAR International Union of Pharmacology
- LH luteinising hormone
- LXR liver X receptor
- MAOI monoamine oxidase inhibitor
- MDDR MDL Drug Database Report
- mRNA messenger RNA
- MS mass spectrometry
- NCE New chemical entity
- NIH (US) National Institutes of Health
- NO nitric oxide
- PACAP pituitary adenylyl cyclase-activating polypeptide
- PCR polymerase chain reaction
- PDE5 phosphodiesterase type
- PPAR peroxisome proliferator-activated receptor
- RAR retinoic acid receptor
- REOS rapid elimination of swill
- RFLP restriction fragment length polymorphism
- RISC RNA-induced silencing complex
- RNAi RNA interference
- RTECS Registry of Toxic Effects of Chemical Substances
- RXR retinoid X receptor
- SAR structure-activity relationship
- siRNA small interfering RNA
- SOD superoxide dismutase
- SNP single nucleotide polymorphism
- T3 triiodothyronine
- THC ?9-tetrahydrocannabinol
- TNF tumour necrosis factor
- tRNA transfer RNA
- USAN United States Approved Name
- VIP vasoactive intestinal polypeptide
- WDI World Drug Index