The document discusses drug targets and strategies for identifying new targets. It notes that most drug targets are proteins, especially receptors, enzymes, and transporters. Two main approaches to identifying targets are analyzing disease pathways and mechanisms of existing drugs. New genomics strategies analyze gene expression changes and use gene knockout studies in model organisms to validate potential targets involved in disease processes. Estimates suggest hundreds of druggable targets remain to be discovered in the human genome.

1. UNIT4.1

2. DRUG TARGETS
• The molecular recognition site to which the drug will bind.
• For the great majority of existing drugs the target is a protein molecule, most commonly a
receptor, an enzyme, a transport molecule or an ion channel, although other proteins such
as tubulin and immunophilins are also represented.
• The search for new drug targets is directed mainly at finding new proteins although
approaches aimed at gene silencing by antisense or siRNA have received much recent
attention.
• The principle of drug discovery based on identified ) targets became established, the
pharmaceutical industry has recognized the importance of identifying new targets as the
key to successful innovation.

3. THE NATURE OF EXISTING DRUG TARGETS
• 120 drug targets accounted for the activities of compounds used therapeutically, and
estimated that 600 - 1500 druggable targets exist in the human genome.
• 100–150 high-quality targets in the human genome might remain to be discovered.
• a recent analysis of 216 therapeutic drugs registered during the decade 2000–2009
showed that 62 (29%) were first in class compounds directed at novel human targets
• Most anti-infective drugs have come from natural products, reflecting the fact that
organisms in the natural world have faced strong evolutionary pressure, operating over
millions of years develop protection against parasites
• The human targets of the 626 drugs, where they are known Of the 125 known targets,
the largest groups are enzymes and G protein coupled receptors, each accounting for
about 30%, the remainder being transporters, other receptor classes, and ion channels.

5. THE NATURE OF EXISTING DRUG TARGETS
• The human genome is thought to contain about 1000 genes in the GPCR family, of which
about one third could be odorant receptors
• The therapy of infectious diseases, ranging from viruses to multicellular parasites, is one
of medicine’s greatest challenges
• Current antibacterial drugs – the largest class – originate mainly from natural products
(with a few, e.g. sulfonamides and oxazolidine diones, coming from synthetic compounds)
first identified through screening on bacterial cultures, and analysis of their biochemical
mechanism and site of action came late
• . For the 142 current anti-infective drugs which include antiviral and antiparasitic as well
as antibacterial drugs approximately 40 targets (mainly enzymes and structural proteins) at
the biochemical level, only about half of which have been cloned

6. TARGET IDENTIFICATION
Two main routes have been followed so far:
• Analysis of pathophysiology
• Analysis of mechanism of action of existing therapeutic drugs.
Analysis of pathophysiology
• first understand the pathway leading from the primary disturbance to the develop
appearance of the disease phenotype, then identify particular biochemical steps
amenable to therapeutic intervention, then select key molecules as targets
• the steps in purine and pyrimidine biosynthesis and selected the enzyme dihydrofolate
reductase as a suitable target led to a remarkable series of therapeutic breakthroughs in
antibacterial, anticancer and immunosuppressant drugs.

8. TARGET IDENTIFICATION
Analysis of mechanism of action of existing therapeutic drugs.
• The identification of drug targets by the ‘backwards’ approach – involving analysis of the
mechanism of action of empirically discovered therapeutic agents – has produced some
major breakthroughs in the past
• Its relevance is likely to decline as drug discovery becomes more target focused, though
natural product pharmacology will probably continue to reveal novel drug targets.

10. NEW STRATEGIES FOR IDENTIFYING DRUG TARGETS
The main points at which drugs may intervene along the
Pathway from genotype to phenotype,
Namely by altering gene expression,
By altering the functional activity of gene
Products, or by activating compensatory
Mechanisms.
• As changes in gene expression or the
Activation of compensatory mechanisms are themselves indirect effects
• It provides a useful framework for discussing some of the newer genomics based approaches.
• A useful account of the various genetic models that have been developed in different
organisms for the identification of new drug targets, and elucidating the mechanisms of action
of existing drugs

11. THE GENOME
• Understanding of the disease mechanisms in the major areas of therapeutic challenge, such as Alzheimer’s
disease, atherosclerosis, cancer, stroke, obesity, etc., is advancing rapidly, and new targets are continually
emerging.
• But this is generally slow, painstaking, hypothesis driven work, and there is a strong incentive to seek shortcuts
based on the use of new technologies to select and validate novel targets, starting from the genome.
• all drug targets are proteins, and are, therefore, represented in the proteome, and also as corresponding genes
in the genome
• one gene ---- one protein ------- one drug target
• ’Disease genes’, i.e. genes, mutations of which cause or predispose to the development of human disease.
• ’Disease modifying’ genes. These comprise (a) genes whose altered expression is thought to be involved in the
development of the disease state; and (b) genes that encode functional proteins, whose activity is altered (even
if their expression level is not) in the disease state, and which play a part in inducing the disease state.
• ’Druggable genes’, i.e. genes encoding proteins likely to possess binding domains that recognize druglike small
molecules. Included in this group are genes encoding targets for existing therapeutic and experimental drugs.
These genes and their paralogues (i.e. closely related but nonidentical genes occurring elsewhere in the
genome) comprise the group of druggable genes.

12. • Disease genes
• The identification of genes in which mutations are associated with particular diseases has a
long history in medicine starting with the concept of ‘inborn errors of metabolism’ such as
phenylketonuria
• None of the gene products identified appears to be directly ‘targetable’
• The most promising field for identifying novel drug targets among diseaseassociated
mutations is likely to be in cancer therapies, as mutations are the basic cause of malignant
transformation and real progress is being made in exploiting our knowledge of the cancer
genome
• identifying disease genes may provide valuable pointers to possible drug targets further
down the pathophysiological pathway, even though their immediate gene products may not
always be targetable.
• The identification of a new disease gene often hits the popular headlines on the basis that
an effective therapy will quickly follow, though this rarely happens, and never quickly.

13. • Disease-modifying genes
• many nonmutated genes that are directly involved in the pathophysiological pathway leading to the disease
phenotype.
• The phenotype may be associated with over or under expression of the genes, detectable by expression
profiling or by the over or underactivity of the gene product –
• for example, an enzyme – independently of changes in its expression level.
• This is the most important category in relation to drug targets, as therapeutic drug action generally occurs by
changing the activity of functional proteins, whether or not the disease alters their expression level.
• Two main approaches are currently being used, namely gene expression profiling and comprehensive gene
knockout studies
Gene expression profiling
• a guide to new drug targets is that the development of any disease phenotype necessarily involves changes in
gene expression in the cells and tissues involved.
• Long term changes in the structure or function of cells cannot occur without altered gene expression, and so a
catalogue of all the genes whose expression is up or downregulated in the disease state will include genes
where such regulation is actually required for the development of the disease phenotype

14. • DNA microarrays (‘gene chips’) are most commonly used in gene expression profiling , their
advantage being that they are quick and easy to use.
• They have the disadvantage that the DNA sequences screened are selected in advance, but this is
becoming less of a limitation as more genomic information accumulates.
• They also have limited sensitivity, which means that genes expressed at low levels – including,
possibly, a significant proportion of potential drug targets – can be missed
• Methods based on the polymerase chain reaction (PCR), such as serial analysis of gene expression
• On the basis of prior biological knowledge, genes that might plausibly be critical in the pathogenesis
of the disease can be distinguished from those (e.g. housekeeping genes, or genes involved in
intermediary metabolism) that are unlikely to be critical
• Anatomical studies can be used to identify whether candidate genes are regulated in the cells and
tissues affected by the disease.
• Time course measurements reveal the relationship between gene expression changes and the
development of the disease phenotype
• The effects of drug or other treatments can be studied in order to reveal genes whose expression is
normalized in parallel with the ‘therapeutic’ effect.

15. • Gene knockout screening
• Another screening approach for identifying potential drug target genes, based on
generating transgenic ‘gene knockout’ strains of mice,
• A knockout, as related to genomics, refers to the use of genetic engineering to inactivate
or remove one or more specific genes from an organism.
• create knockout organisms to study the impact of removing a gene from an organism,
which often allows to then learn about that gene's function.
• using transgenic gene knockout technology to confirm the validity of previously well -
established drug targets is not the same as using it to discover new targets.
• Success in the latter context will depend greatly on the ability of the phenotypic tests that
are applied to detect therapeutically relevant changes in the knockout strains.
•

17. • ’Druggable’ genes
• it must possess a recognition site capable of binding small molecules
• the protein is likely to possess a binding site for a small molecule, irrespective of
whether such an interaction is likely be of any therapeutic value.
• To be useful as a starting point for drug discovery, a potential target needs to
combine ‘draggability’ with disease modifying properties.
• The discovery and exploitation of new targets is considered essential for
therapeutic progress and commercial success in the long term.
• Estimates from genome sequence data of the number of potential drug targets,
defined by disease relevance and ‘druggability’, suggest that from about 100 to
several thousand ‘druggable’ new targets remain to be discovered.
• The uncertainty reflects two main problems: the difficulty of recognizing
‘druggability’ in gene sequence data, and the difficulty of determining the relevance
of a particular gene product in the development of a disease phenotype.