Biological Drug Targets
• How do brain cells communicate with one another to
produce thoughts, feelings, and behaviour?
• Neurotransmission begins when one brain cell releases a
neurochemical into the synapse, or the space in between neurons.
But for a neighboring cell to “pick up” the message, that
neurochemical must bind with one of its receptors.
• It’s a bit like a game of catch.
• The first cell releases the neurochemical into the synapse and the
receiving cell must catch it before it can read it and respond. The
receptor is the part of the cell that does the catching.
Receptors as drug targets:
• Receptor proteins are embedded in the cell membrane in such a way that their
active site-containing small portion protrudes from the membrane's inner or
outer surface.
• They attract chemical messengers like hormones, neurotransmitters, mediators
and drugs. Receptors are complex proteins having high selectivity of recognition
and attachment of the binding molecule.
• It also has multiple sites that can bind to different parts of the same molecule.
They exhibit reversible binding spending on the conditions.
• These properties make the receptor a potential target for developing drugs to
control biological effects.
• Receptors are identified by the specific neurotransmitters/hormones which
activates them.
Functioning of receptor proteins:
• Chemical messengers are substances that are sent to receptor proteins'
binding sites. The shape of the receptor site alters to accommodate a
message.
• As a result, a chemical messenger sends a message to the cell without really
entering it.
The steps involved in this process are as follows
1. Receptors bind to the specific chemical messenger.
2. The receptor's shape changes when the chemical messenger is attached.
3. The receptor regains its structure once the chemical messenger is removed.
Receptor activation
How does binding site change shape ?
The hypothetical binding site contains three binding regions which contain functional
groups that are complimentary to the binding groups of the messenger. The
messenger fits into the binding site such that intermolecular interactions take place
between the messenger’s binding groups and the receptor’s binding regions.
Ion channels are specific for certain ions.
For example there are different cationic ion channels for sodium (Na+), potassium (K+), and
calcium (Ca2+) ions. There are also anionic ion channels for the chloride ion (Cl− ). The ion
selectivity of different ion channels is dependent on the amino acids lining the ion
channel. The mutation of just one amino acid in this area is sufficient to change a cationic-
selective ion channel to one that is selective for anions.
Structure
( a ) Pentameric structure of ion channels
(transverse view). I, ion channel controlled by a
( b ) Transverse view of I, including
nicotinic cholinergic receptor; II, ion channel
controlled by a glycine receptor. The coloured transmembrane regions.
circles indicate ligand binding sites.
Opening of ion channel (gating)
• Important drug targets in medicinal chemistry.
• 30% of all drugs on the market act by binding to these receptors.
• In general, they are activated by hormones and slow-acting neurotransmitters.
• E.g muscarinic receptor, adrenergic receptors, opioid receptors
• The response from activated G-protein-coupled receptors is measured in
seconds. This is slower than the response of ion channels, but faster than the
response of kinase-linked receptors.
• There are a large number of different G-protein-coupled receptors interacting
with important neurotransmitters, such as acetylcholine, dopamine, histamine,
serotonin, glutamate, and noradrenaline
The kinase-linked receptors are activated by a large number of
polypeptide hormones, growth factors, and cytokines.
Loss of function of these receptors can lead to developmental
defects or hormone resistance. Overexpression can result in
malignant growth disorders.
Receptor for insulin, and receptors for various cytokines and growth
factors.
• Drugs that mimic the natural messengers and activate receptors are
known as agonists.
• Drugs that block receptors are known as antagonists
What determines whether a drug acts as an agonist or an antagonist,
and is it possible to predict whether a new drug will act as one or the
other?
