Structure and function - L2

Question 1

what does an agonist do?

Answer 1

mimics the natural neurotransmitter and binds in a way to activate the receptor

Question 2

what is a receptor

Answer 2

protein molecules embedded in the cell membrane. Selective binding sites for chemical messengers - sends signal.
Messenger binds to receptor in induced fit then changes shape

Question 3

what are the 3 types of membrane receptors?

Answer 3

G protein coupled
ion channel
kinase linked

Question 4

what does each membrane receptor do?

Answer 4

Kinase linked - activate enzymes directly
G protein coupled - respond to hormones and slow acting NTs
ion channel - control movement of ions across membrane

Question 5

what are the 3 things needed for agonists?

Answer 5

must have correct binding groups
binding groups in correct position
drug must be correct size for binding site

Question 6

what binding groups are required for agonists?

Answer 6

all binding interactions

• VDW collectively strong - electrostatic
• NTs must be able to bind, pass on message and leave binding site quickly so need all the binding interactions to ensure this happens.
• even if we have the binding groups, if they are in the wrong position then the receptor activation will fail so need to consider this too

Question 7

Why is it important to have proper size of molecules in agonists?

Answer 7

Presence of correct binding groups in correct position is important. It must also be of correct size and shape to allow binding groups to align with the binding regions within the target

Question 8

what is an antagonist?

Answer 8

binds to receptor in a way that doesn’t activate it - it inhibits binding of natural messenger

Question 9

what are the 2 approaches of antagonist activity?

Answer 9

1- use molecule that fits perfectly into the AS- use natural binding regions to mimic binding of natural substrate - has enhanced binding over natural substrate and fits perfectly into it so there is no induced fit and no biological activity

2. use alternative binding regions within the AS; inhibit binding of natural substrate and result in an alternative d fit, deactivating the receptor.

Question 10

what is an inverse agonist?

Answer 10

has the same effect as an antagonist but it can also prevent the activity associated with the natural equilibrium (some receptors have activity in the absence of messenger so an equilibrium exists between active and inactive)

Question 11

what is a partial agonist?

Answer 11

bind to receptor for activation to occur.
Binding may result in a conformational change that is not ideal = decrease in subsequent effects of the receptor.

Partial agonists can utilise different binding regions in the AS to give a different binding profile for the same molecule e.g one mode may show agonist, another may how antagonist - equilibrium between these modes determine level of drug activity

Question 12

what proteins are drug targets?

Answer 12

transport proteins - drug mimics the guest molecule, bind strongly and blocks activity e.g Fluoxetine

Structural proteins - drugs e.g anti viral - prevents conformational change

Tubulin - cancer - binds to inhibit polymerisation or stabilise the microtubule and inhibit depolymerisation

protein protein interactions - target key amino acids involved in biological processes - Nutlin 2 anti cancer drug

Question 13

what is an allosteric site?

Answer 13

an alternative site on an enzyme - inhibitors can bind to this (induced fit) and causes a conformational change of the enzyme which results in the natural substrate being unable to bind. It uses a feedback control mechanism

Question 14

what is competitive reversible inhibition?

Answer 14

binds to active site, inhibits or switches off enzyme function. It is reversible because an equilibrium exists between bound and un-bound drug. Increasing the concentration of natural substrate CAN displace the drug

Question 15

what is irreversible inhibitor?

Answer 15

binds irreversibly by forming covalent bonds with amino acid residues e.g cysteine and serine.
E.g anti obesity drug orlistat

Question 16

Why is reversible inhibitor preferred over irreversible?

Answer 16

Irreversible inhibitors contain reactive functional groups which an react with biological molecules to produce toxic side effects. Also, irreversible aren’t competitive as they are permanently bound to the AS, there fore it can lead to a build up of substrates resulting in toxic S/E.
Example- MAOIS and tyramine

Question 17

what is uncompetitive inhibitor?

Answer 17

binds reversibly to the enzyme-substrate complex.
Increasing [substrate] doesn’t affect inhibition like competitive - it actually depends on sufficient levels of substrate to bind to it

Question 18

What is non competitive inhibitor?

Answer 18

binds to an allosteric site to inhibit activity - it doesn’t inhibit substrate binding. It just changes the position of amino acids in the enzyme to slow the rate. e.g Nevirapine anti viral drug

Question 19

what is a transition state analogue?

Answer 19

inhibitor mimics the transition state - binds stronger than the substrate to give irreversible inhibition
e.gRenin inhibitors

Question 20

what is a suicide substrate?

Answer 20

harmless molecule until they’re converted within the active site to a highly reactive species which can form covalent bonds with amino acids in the active site.

Question 21

why is trifluoroanaline a suicide substrate?

Answer 21

When we introduce trifluoroanaline - there is a point at which we loose F- (good LG) and it goes into the AS to form a covalent bond (irreversible) - it becomes reactive when F- is lost into the AS which is characteristic of a suicide substrate. If we had a hydrogen this would not happen, H- is bad LG, wouldn’t become reactive.