Biological Systems interacting with drug substances

Question 1

At a molecular level, what type of biological molecules are likely to be involved as drug targets?

Answer 1

Lipids, carbohydrates, proteins, nucleic acids.

Question 2

What biological molecule do drugs MAINLY act on?`

Answer 2

Proteins or nucleic acids.

Question 3

How do lipids work as drug targets?

Answer 3

Involves the disruption of the lipid structure of cell membranes, hence modifying the structure of the cell

Question 4

What are enzymes?

Answer 4

Biological catalysts for cell’s chemical reactions.

Question 5

Explain how irreversible inhibition works?

Answer 5

Irreversible inhibitors form covalent bonds with functional groups at or near the enzyme active site. Because covalent bonds are strong bonds and not easily broken, the inhibitor becomes permanently attached to the active site, thus permanently modifying the active site.

Question 6

Why are irreversible inhibitors not used as drugs?

Answer 6

Molecules with irreversible inhibitory action are not used as drugs because they tend to be too toxic.
But have been used to map the enzyme’s active site because they are permanently bound to the active site.

Question 7

Describe reversible competitive inhibition.

Answer 7

Competitive inhibition is when the inhibitor and the normal substrate compete for binding at the enzyme active site. This type of inhibition can be overcome by increasing the concentration of the normal substrate.

Question 8

Describe reversible non-competitive inhibition.

Answer 8

Non-competitive inhibition is where the inhibitor does not bind to the enzyme active site and so is not in competition with the normal substrate for the active site. But can cause conformational changes to the enzyme preventing the substrate from binding to active site.

Question 9

What type of inhibitor is aspirin? How does it work?

Answer 9

Irreversible inhibitor.
Aspirin irreversibly binds to and inhibits cyclooxygenase by acetylation of serine hydroxyl group at the active site by a transesterification reaction.

Question 10

What is cyclooxygenase?

Answer 10

An enzyme responsible for production of prostaglandins and thromboxane.

Question 11

What’s an example of a competitive reversible inhibitor? How does it work?

Answer 11

Statins such as lovastatin and simvastatin.

They inhibit the activity of HMG-CoA reductase which is an enzyme involved in the biosynthesis of cholesterol.

Question 12

What’s an example of a non-competitive reversible inhibitor? How does it work?

Answer 12

Donepezil. An acetylcholinesterase inhibitor given to patients with Alzheimer’s to slow down the loss of cognitive function (by having low levels of Ach).
Donepezil binds to allosteric site = non-competitive.

Question 13

What happens when an endogenous ligand binds to a receptor?

Answer 13

This interaction results in a specific biochemical or physiological response. This response is referred to as signal transduction.

Question 14

Receptors are classified into four main types known as superfamilies. What are these superfamilies?
Describe each of them.

Answer 14

1. Ion channel receptors - where endogenous ligands are fast neurotransmitters.
2. G-protein-couple-receptors - where endogenous ligands are hormones and slow neurotransmitters.
3. Tyrosine kinase receptors - with insulin and growth factors as endogenous ligands.
4. Nuclear receptors - with steroid hormones, thyroid hormones and certain vitamins as endogenous ligands.

Question 15

What is the transmission speed of ion channel receptors?

Give two examples of ion channel receptors.

Answer 15

Fast transmission - operating in a millisecond timeframe.
Nicotinic Ach receptor - an excitatory ion channel receptor. E.g. Atracurium besilate.
GABA-A receptor - an inhibitory ion channel receptor in the brain E.g. Benzodiazepines.

Question 16

What is the transmission speed of GPCRs?

Give two examples of drugs which interact with GPCRs.

Answer 16

Slow transmission - operating in a second timeframe.
Salmeterol - B2-adrenergic agonist.
Ranitidine - histamine H2 antagonist.

Question 17

What happens when a ligand binds to a GPCR?

Answer 17

Ligand binding at GPCRs causes activation of a G-protein complex which dissociates and activates a membrane-bound enzyme, releasing a secondary messenger.

Question 18

What are tyrosine kinase receptors involved in?

Answer 18

Involved in signal transduction of insulin and polypeptide growth factors and control of cell growth, cell division and cell differentiation.

Question 19

What does signal transduction in tyrosine kinase receptors involve?

Answer 19

Signal transduction involves the dimerisation of the receptors, autophosphorylation of tyrosine residues and interaction with S2 domains of intracellular proteins.

Question 20

What is the transmission speed of tyrosine kinase receptors?

Answer 20

Very slow transmission - minutes to hours.

Question 21

Why are tyrosine kinase receptors good targets for anti-cancer therapy?

Answer 21

Ligand activation changes cells from resting state to cell division cycle. This makes these receptors important drug targets for anti-cancer drugs.

Question 22

Where are nuclear receptors found and what do they interact with (ligands)?

Answer 22

Nuclear receptors are found inside the cell - their ligands must be able to enter the cell.
They interact mainly with hormones.

Question 23

Describe the process of a ligand binding to the receptor.

Answer 23

An example of a ligand binding to the receptor is a hormone. A hormone binds to the receptor and causes a conformational change, exposing the DNA binding region. This allows for the binding of DNA, leading to the activation of specific genes and to protein synthesis.

Question 24

What is the transmission speed of nuclear receptors?

Answer 24

Very slow transmission - time frame of this is un the order of hours.

Question 25

What drug is known as anti-oestrogen? Why is this?

Answer 25

Tamoxifen is known as anti-oestrogen because it acts as an antagonist at oestrogen receptors, preventing the binding of estradiol. Binding of estradiol causes increase in growth of cancer cells.

Question 26

What are the role of microtubules and how are they formed?

Answer 26

Microtubules are involved in cell division and the maintenance of cell structure, formed by the polymerization of the structural protein, tubulin.

Question 27

Describe what happens with microtubules in cell division.

Answer 27

Microtubules depolymerise then repolymerise, producing a spindle which forms the frame on which the chromosomes can be transferred to daughter cells.

Question 28

In simple terms, state how the drug prevents the action of microtubules. Give an example of an inhibitor.

Answer 28

Drugs target protein tubulin by binding to it, inhibiting the polymerisation into microtubules and prevents mitosis. Paclitaxel = anti-cancer agent.

Question 29

What are transport proteins and what is their role?

Answer 29

Transport proteins are cell membrane proteins whose role is to transport endogenous molecules across the cell membrane (transport molecules from extracellular side to intracellular = uptake).

Question 30

What is the issue associated with transport proteins which move molecules into the cell from outside?

Answer 30

Uptake of endogenous molecules from outside the cell resulting in reduced contact and interaction with the relevant receptors on the target cell i.e. not able to bind to target cell so therapeutic effect is not achieved.

Question 31

What is the effect of drug molecules on transport proteins?

Answer 31

Drug molecules can bind to transport proteins to inhibit the uptake process allows a therapeutic effect due to prolonged presence of endogenous molecules within the vicinity of the receptor.

Question 32

Give an example of a reuptake inhibitor which binds to transport proteins.

Answer 32

Tricyclic antidepressants. Block the reuptake of endogenous amines such as NA and serotonin.

Question 33

How does the majority of drugs target lipids?

Answer 33

By interfering with the lipid structures of the cell membrane resulting in disruption of cell membrane.

Question 34

An irreversible inhibitor is aspirin. What's the benefit of taking a small dose of aspirin?

Answer 34

Low doses of aspirin are more effective in reducing TXA2 synthesis than prostacyclin synthesis. Also, low doses reduces unwanted side effects e.g. GI damage.