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LIFE207 > Drug Binding And Receptor Structure > Flashcards

Drug Binding And Receptor Structure Flashcards

1
Q

What is Paul Ehrlich’s quote?

A

“A drug will not work unless it is bound”

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2
Q

What action can cause a biological event?

A

Response - agonist

Prevent response - antagonist

Chemical change - substrate

Prevent chemical change - inhibitor

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3
Q

What chemical bonds are involved in drug binding, order them ini their relative strengths?

A

Covalent bonds
Ion-ion
Ion-dipole
Hydrogen
Van der Waals
Hydrophobic bond

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4
Q

What functional groups does acetyl choline have?

A
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5
Q

What is myasthenia gravis?

A

Disease characterised by progressive muscle weakness

Antibodies against nicotinic receptors in NMJ

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6
Q

What does a high EC50 mean?

A

That the compound is less potent

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7
Q

What is the equipotent molar ratio equal to?

A

EC50 of test compound / EC50 ACh

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8
Q

What does a EMR greater than 1 mean?

A

That the test compound is less potent than ACh

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9
Q

What does a EMR less than 1 mean?

A

That the test compound is more potent than ACh

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10
Q

What functional group on ACh is crucial for activity on both nicotinic and muscarinic receptors?

A

The quaternary ammonium ion

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11
Q

Why is it important for choline to have no effect at nicotinic or muscarinic receptors?

A

Because ACh is regulated by its breakdown into choline and acetic acid, choline is then taken back up into pre-synaptic nerve.

If it had any effect there would be no point in ACh’s regulation

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12
Q

Why is propionyl choline favourable as a drug molecule? What other molecule gives selectivity?

A

Because it is more active at nicotinic receptors and less active at muscarinic receptors than ACh

Hence bringing selectivity for nicotinic receptors as EMR is >1

Butyryl choline has an EMR of ≈ 1 at nicotinic receptors, but at muscarinic receptors its activity is significantly lower, hence bringing selectivity.

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13
Q

What functional groups are essentials for nicotinic receptors on ACh?

A

Quaternary ammonium

Ester Oxygen

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14
Q

What functional groups are essentials for muscarinic receptors on ACh?

A

Quaternary ammonium

Ether Oxygen

Ester methyl

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15
Q

What’s the definition of the pharmacophore of a molecule?

A

The chemical signature of the chemical of interest that is critical for its interactions with it target

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16
Q

How does the activity of muscarine at muscarinic receptors compare to the activity of ACh?

A

It has an EMR of 0.33 - i.e. 2 thirds more potent than ACh

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17
Q

How does nicotine’s activity at nicotinic receptors compare to that of ACh?

A

Nicotine is 8 times less effective than ACh at nicotinic receptors, still binds and causes a response but it is less effective

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18
Q

What receptors does morphine act at?

A

Mediated by µ-opioid receptors

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19
Q

What compounds are found in cobra venom that interact with nicotinic receptors?

A

Alpha-bungarotoxin

Cobratoxin

Causes paralysis of the organisms

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20
Q

Why are mongooses significant?

A

As they prey on cobras, hence must have evolved some kind of biologically immunity / defence so that the nicotinic toxins don’t effect then as much

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21
Q

What subunits does the nicotinic receptor posses?

A

2 alpha subunits

1 ß subunit

1 gamma subunit

1 ∂ subunit

22
Q

What subunits of the nicotinic receptor does ACh - and cobra toxins - bind to?

A

Both bind to the alpha subunits

23
Q

What’re the dimensions of the exterior of the nicotinic receptor?

A

80Å wide and 60Å from the cell membrane

24
Q

How many hydrophobic domains are there in the structure of the nicotinic receptor?

A

4 hydrophobic domains - membrane spanning regions

25
Q

How many amino acids are extracellular in the structure of the nicotinic receptor?

A

First 200 amino acids are extracellular

26
Q

What’s the significance of the hydrophobic domains within the nicotinic

A

The hydrophobic transmembrane domains are the gating mechanism that allow Na+ ions through into the cell/tissue

27
Q

What is affinity labelling?

A

When a compound which is known to bind to a receptor is put under UV light to form a covalent bond with the receptor.

This can then be studied

28
Q

What amino acid residues does DDF bind to in the nicotinic receptor site? What’s the importance of this?

A

Tryptophan, tyrosine and cysteine

Hence these residues are important in the binding mechanism of acetyl choline to the nicotinic receptor

29
Q

How has the mongoose evolved to avoid paralysis by a cobra’s venom?

A

It has amino acid sequence changes so that acetyl choline can still bind and interact with the receptor, but bungarotoxin, etc, now have a negligible effect due to the changes in amino acid residues - 4/5 amino acids are different

30
Q

What, and how many, amino acids are critical to ACh’s binding to the nicotinic receptor?

A

2 x tryptophans

4 x tyrosines

2 x cysteines

31
Q

What’s the purpose of the +vely charged quaternary ammonium on ACh?

A

+ve charge has no effect on actual binding to receptor as none of the amino acids have an overall -ve charge

Likely that the ionic interaction brings ACh closer to the protein, then other residues pull ACh into the binding site and cause a response

32
Q

How far is the binding site from the cell surface?

A

1.5nm away - fairly far

33
Q

How many transmembrane domains are there for the muscarinic receptor?

A

7 transmembrane alpha helices

34
Q

What receptor is G-protein coupled, nicotinic or muscarinic?

A

Muscarinic is G-protein coupled

35
Q

What is the intracellular and extracellular terminal of the muscarinic receptor?

A

Extracellular = NH2 terminal

Intracellular = COOH terminal

36
Q

How many amino acids are conserved in the muscarinic receptor?

A

145 conserved amino acids

37
Q

How does the muscarinic receptor work?

A

ACh binds

Conformational changes activate the G-protein

G-protein bind to an effector molecule which then causes muscular contraction

38
Q

Which loop of the muscarinic receptor is largely variable?

A

The 3rd intracellular loop (157-240) - unknown reason

39
Q

How is ACh binding initiated for the muscarinic receptor?

A

Initiated by ion-ion interaction, ACh binds in hydrophobic pit within the receptor

40
Q

What amino acid residues are important for ACh binding at the muscarinic receptor?

A

1 x aspartate - slightly -ve, ionic interaction

4 x tyrosines

2 x threonine

41
Q

Where is the binding site of ACh for the muscarinic receptor?

A

Within the cell membrane; ‘hydrophobic pit’

42
Q

What’re the 2 types of cholinesterases?

A

True cholinesterase - acetylcholinesterase, found in nerve endings, skeletal muscle. Has highest affinity for ACh

Pseudo cholinesterase - Butyrylcholinesterase, found in plasma, liver, intestine. Detoxification? Has a lower affinity for ACh but still hydrolyses it.

43
Q

How does acetylcholinesterase break down ACh?

A

There are 2 sites, anionic site and esteratic site

44
Q

What amino acid residues are present in the 2 binding sites of AChE?

A
45
Q

What interaction is present at the anionic site?

A

Cation-pi bond (42-92kJ/mol)

Stronger than ionic interaction

46
Q

What happens at the esteratic site?

A

Once ACh is bound to the anionic site, the Glu-Ser-Ala -OH residue attacks the carbonyl and breaks the ester bond

Choline is formed and is re-up-taken at pre-synaptic nerve

Water then attacks at the carbonyl bound at esteratic site to give acetic acid

47
Q

What is the rate limiting step for ACh hydrolysis?

A

The RDS is the hydrolysis/removal of acetic acid from the esteratic site of AChE.

48
Q

Give an example of a molecule that inhibits AChE reversibly

A

Edrophonium - has quaternary ammonium reversibly binding to anionic site, but isn’t broken down and hence blocks ACh from entering the enzyme, hence preventing ACh’s breakdown

Used in diagnosis

49
Q

Give an example of a molecule that time-dependent irreversibly inhibits AChE

A

Neostigmine - same attraction through cation-pi interaction from a quaternary ammonium

However, carbamylation occurs - serine OH attacks carbonyl. This is 1 million times slower than the metabolism of acetyl choline.

Irreversible because it stays for literal years so can be problematic, but it is eventually broken down

Used to treat muscle weakness

50
Q

Give an example of a molecule that inhibits AChE irreversibly

A

Organophosphorus compounds - Novichok agents, DYFLOS. Chemical warfare nerve agent

Serine - OH attacks P and cannot be broken down

51
Q

What is the antidote for a Novichok agent exposure?

A

Pralidoxime iodide - interacts with tryptophan in anionic site and removes organophosphorus compound from esteratic site of the enzyme

LIFE207 (9 decks)

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