Molecular Drug Targets

Question 1

How to drugs elicit an action?

Answer 1

Drugs must bind a molecular target. These targets can be enzymes, carrier molecules, ion channels or receptors.

Question 2

What are some non-receptor targets for drugs?

Answer 2

• Ion channels (ie. Ca2+ channels)
• Enzymes (ie cyclo-oxygenase)
• Carrier molecules (ie. serotonin uptake)
• DNA
• Osmotic pressure
• Direct actions - there are fewer drugs like this/AKA we do not know how it works

Question 3

What are receptors?

Answer 3

Receptors are the sites of action of neurotransmitters, hormones (and autocoids/autacoids), many second-messengers and many drugs.

A receptor is a biological macromolecule or complex that binds another molecule and initiated or modulates signaling or effector activity within a cell.

Question 4

Explain:
Ligands?
Binding sites?
Agonists & Antagonists?

Answer 4

A receptor is a biological macromolecule or complex that binds another molecule and initiated or modulates signaling or effector activity within a cell.
A molecule that binds to a receptor is a ligand. Ligands bind to binding molecules at a binding site. A ligand that binds to a receptor and activates it is an agonist. A ligand that binds to a receptor without activating it will act as an antagonist.
All receptors are binding molecules but not all binding molecules are receptors.

Question 5

What are the 4 categories of receptors?

Give their time scale and an exmaple.

Answer 5

1) Ligand-gated Ion Channels - act in milliseconds - example: Nicotinic ACh receptor
2) G Protein-coupled receptors - act in seconds - example: Muscarinic ACh receptor
3) Kinase linked receptors - act in hours - example: cytokine receptors
4) Nuclear receptors - act in hours - example: oestrogen receptor

Question 6

Explain Ligand-gated Ion channels.

Answer 6

Agonist binds directly to and directly regulates the opening of an ion channel. They open rapidly, the time scale for effect is miliseconds

• ie. nicotinic recetors (multimeric, 5 subunits, α2βγδ)
• Ach binds to α subunits
• Na+ channel opens
• Na+ entry stimulates action potential and contraction

Question 7

Explain G Protein Coupled receptors?

Answer 7

Receptors consisting of 7 transmembrane segments (in an antipathic alpha-helix); mostly found on the cell surface (but rhodopsin lives inside cone/rod cells in the eyes and signals much faster than the typical GPCR); it is linked to an effector (effector may be an ion channel, enzyme, transporter or regulator of gene transcriptor) by a G-protein (these G-proteins exist in many forms)
This is the most common receptor/protein in the human genome and the receptor pathway generally acts in seconds to minutes.
The ligand binds and activates the G-proteins, which can have different affinities to the receptors. The activated G-proteins can activate/inactivate ion channels or enzymes.
Different receptors can have different mechanisms and reinforcing or opposing effects
-ie. ACh slows heart rate, NA speeds heart rate
There are lots of GPCRs.

Question 8

Explain Kinase-linked receptors

Answer 8

These are usually tyrosine or serine kinases. They phosphorylate proteins which is a common/important manner of regulating enzymatic activity within the cell. It can turn on/turn off enzymes.
The agonist binds to extracellular domain of a transmembrane protein and activates enzymatic activity of the protein’s cytoplasmic domain often after dimerisation).
They phosphorylate proteins (often including themselves) and activators are often large peptides or proteins (ie. growth hormone)

Question 9

Explain Nuclear receptors.

Answer 9

Signaling ligand enters the cell, binds and activates intracellular receptor (often in the cytoplasm or the nucleus). Some interact with nuclear binding sites or things that effect the nuclear binding sites. The receptor regulates gene transcription.
- glucocorticoids receptor activation inhibits cyclooxygenase gene transcription