Drug discovery: finding a lead

Choosing a disease
To concentrate on diseases where there is a need for new
drugs.

Choosing a drug target

Drug targets
To identify a suitable drug target (e.g. receptor, enzyme,
or nucleic acid).

Agonists or antagonists should be designed for a

particular receptor or whether inhibitors should be
designed for a particular enzyme.
 Agonists or antagonists
For example
agonists of serotonin receptors are useful for the treatment
of migraine,
while antagonists of dopamine receptors are useful as
antidepressants.

Tricyclic antidepressants , such as desipramine, are known

to inhibit the uptake of the neurotransmitter
noradrenaline (both a neurotransmitter and a hormone)
from nerve synapses by inhibiting the carrier protein for
noradrenaline.
. However, these drugs also inhibit uptake of a
separate neurotransmitter called serotonin , and the
possibility arose that inhibiting serotonin uptake
might also be beneficial.

A search for selective serotonin uptake inhibitors was

initiated, which led to the discovery of the best-selling
antidepressant drug fluoxetine (Prozac).
Discovering drug targets
In 1970 variety of protein and peptides (enkephelins and
endorphins) (mimic the activity of morphine in
isolated smooth-muscle preparations )are discovered
as own analgesic.

Nitric oxide (chemical messenger)

Orphan receptor (protein that has a similar structure to

other identified receptors but whose endogenous
ligand has not yet been identified.)
Combinatorial and parallel synthesis
Recently discovered drug targets (Caspases enzyme)
Carboplatin (anticancer agent)
Caspases ………enzymes which may prove useful as drug
targets .

family of protease enzymes that catalyse the hydrolysis of

important cellular proteins, and which have been found to
play a role in inflammation and cell death.

Caspases
catalyse the hydrolysis of particular target proteins such as
those involved in DNA repair and the regulation of cell
cycles .
 Agents which promote the activity of caspases and lead to
more rapid cell death might be useful in the treatment of
diseases such as cancer, autoimmune disease, and viral
infections.

carboplatin is an anticancer agent that promotes caspase

activity.

Agents which inhibit caspases and reduce the prevalence of cell

death could provide novel treatments for trauma,
neurodegenerative disease, and strokes.
Active site of caspases contains two amino acids that
are crucial to the mechanism of hydrolysis— cysteine,
which acts as a nucleophile, and histidine, which acts
as an acid–base catalyst.
Reference
Gareth Thomas, Fundamental of medicinal
Chemistry, 2003, John Wiley & Sons Ltd
Graham’s Patrick. An introduction to medicinal
chemistry, fifth edition, Oxford University press