How drugs interact with receptors Flashcards
(95 cards)
1
Q
Are lipid drug targets common or rare?
A
rare
2
Q
What do lipid drug targets aim to do?
A
- disrupt lipid structure–> inderection action on proteins
- form conducting pathways across the membrane–> altering electrochemistry of cell
3
Q
What do DNA drug targets do?
A
- covalently modify DNA bases–> done by intercalating between bases, disrupting reproduction of the cell
4
Q
Do DNA drug targets have specificity and why?
A
Not much because they use binding sites, not receptors
5
Q
What are the relative sizes of drug and receptor?
A
drugs are usually in 100s of Da, whereas receptors are in the 100s of kDa (1000x bigger)
6
Q
How much of a receptor does a drug interact with?
A
a small part
7
Q
How many subunits in a glucocortoid receptor?
A
2
8
Q
What binds to a glucocortoid receptor?
A
steroid hormone
9
Q
what happens when a steroid hormone binds to a glucocortoid receptor?
A
produces energy (binding energy) which causes a conformational affect
10
Q
what are receptors molecularly?
A
proteins
11
Q
what are proteins?
A
Amino acids linked by amide bonds
12
Q
What are the 5 types of Amino Acid side groups?
A
Polar, acidic, aromatic (electron-rich), non-polar and basic
13
Q
what are the 5 types of drug-receptor bond?
A
electrostatic, hydrogen, hydrophobic, van der waals and covalent
14
Q
what are the 3 types of electrostatic bond from strongest to weakest?
A
Ionic
ion- dipole
dipole-dipole
15
Q
are hydrogen bonds directional?
A
no
16
Q
are hydrophobic bonds weak or strong?
A
weak
17
Q
are hydrophobic bonds numerous or few in proteins?
A
numerous
18
Q
what drives hydrophobic bonds?
A
entropy gain
19
Q
How are hydrophobic bonds driven by entropy gain?
A
if have move the hydrophobic molecules closer together, they’ll be fewer interactions with water, therefore higher entropy
20
Q
what causes van der waals?
A
spontaneous dipoles
21
Q
are van der waals strong or weak?
A
weak
22
Q
are van der waals numerous or few in proteins?
A
numerous
23
Q
are covalent bonds strong or weak?
A
strong
24
Q
are covalent bonds rare or common in drugs and why?
A
Rare
because drugs are reversible but covalent bonds often aren’t reversible
25
what part of a protein do drugs bind to?
R-group of the Amino acid or peptide backbone
26
What are enantiomers? (4)
non-superimposable mirror image molecules
Identical physical/chemical properties
differ in rotation of polarised light
a form of stereoisomerism
27
If an enantiomer rotates polarised light clockwise, how is it named? (2)
- d or +
28
if an enantiomer rotates polarised light anticlockwise, how is it named?
- l or -
29
what does the D/L system of classifying enantiomers relate to?
the configuration of a chiral centre to the structure of glyceraldehyde
30
How do you determine if an amino acid enantiomer is D or L?
draw in the fischer projection with the most oxidised carbon at the top.
If the amine group points left, it's L.
if the amine group points right, it's D
31
What does the Cahn Ingold prelog system allow?
3D drawing of a molecule
32
How do you draw and work out if your enantiomer is R or S in the Cahn Ingold prelog system?
- draw the molecule with the chiral carbon in the centre with the lowest priority (lowest atomic number) group facing backwards
- ignoring the lowest priority group number the other 3 groups from 1 to 3 based on priority
- Then draw an arrow going from #1 to #3. If it's clockwise it's R, anticlockwise it's S
33
What is affinity?
How tightly the drug binds to the receptor
34
How is affinity represented?
Dissociation constant (Kd)
35
What is the dissociation constant (Kd)?
the concentration that gives 50% of maximum occupancy
36
In terms of the dissociation constant- the better the fit,
the lower the Kd value
37
what is radioligand binding used for?
screening drugs
38
how is radioligand binding screening done?
- take radioligand form of drug, incubate with some membranes with receptors
- leave to come to equilibrium
- Some/all receptors will be occupied by the radioligand
- separate the bound radioligands from free ones by either centrifugation of filtration
- can see what proportion bound and what proportion didn't
39
what does the Hill- Langmuir isotherm show?
the degree of binding between the ligand/ drug and binding sites
40
write the Hill- Langmuir isotherm equation and what each component is
```
B= Bm. [D] / Kd + [D]
B- drug bound
Bm= Max. binding
Kd- dissociation constant (concentration giving 50% of max binding
[D]- concentration of drug
```
41
when the Hill-Langmuir isotherm equation is plotted on a graph with a linear scale, what does it show?
A rectangular Hyperbole
42
when the Hill-Langmuir isotherm equation is plotted on a graph with a logarithmic scale, what does it show?
A sigmoidal curve
43
what is the Hill-Langmuir isotherm equation similar to?
Michaelis Menten equation (for enzyme kinetics)
44
What does 'p' notation allow?
allows us to avoid dealing with v.small numbers to make things more intuitive
45
How do we go from Kd to pKd?
-logKd (similar to pH scale)
46
as affinity increases, how does pKd change?
it also goes up
47
what does the 'p' in p notation stand for?
potence
48
how is pKd distributed?
normally (making it useful for stats tests)
49
what do signalling molecules almost always do to their target receptor?
activate it
50
What's an agonist?
a substance (natural or synthetic) that activates a receptor
51
When plotting concentration-response relationships how should concentration be logged?
as a log to give the sigmoidal curve (works best for the wide-range of drug concentrations)
52
What is EC50?
the concentration of drug which gives 50% of the maximum effect
53
what is a measure of potency?
EC50
54
what is Emax?
the maximum response achievable from a drug
55
write the equation showing the relationship between concentration and effect and what each component is
```
E= Emax. [D]/ EC50 + [D]
E- effect
Emax- max. effect
D- drug conc.
EC50- conc. giving 50% of max effect
```
56
What is potency?
the concentration of drug required to give a certain response
57
How are potency and EC50 related?
smaller the EC50, the larger the potency (less concentration required to give a certain response)
58
What is a competitive antagonist?
an antagonist binds to the site, however causes no transduction, simply blocks the binding site of the agonist
59
Is competitive antagonism reversible?
yes
60
what's the most common form of antagonism?
competitive
61
write out the Gaddam equation and what the components mean
```
E= Emax. [D] / [D] + EC50 (1+ [B] / KB)
E= effect
Emax.= Max. effect
D= conc. of drug
EC50= concentration required for 50% of max effect
B= antagonist conc
KB= dissociation constant of antagonist
the part in brackets is the concentration ratio
```
62
what does the Gaddam equation show?
when an agonist and antagonist are both present, more agonist is needed to have the same effect as the agonist alone
63
What does the concentration ration (CR) tell us?
the factor we have to increase agonist conc. by to overcome the presence of a competitive antagonist
64
What does the PA2 value indicate?
the concentration of antagonist when double the agonist is required to have the same effect on the receptor as when no antagonist is present
65
What is the inhibition curve?
curve on graph which uses a fixed concentration of agonist and an increasing concentration of agonist against the % of the control response (a downwards curve)
66
what's IC50?
the concentration of antagonist that gives 50% of the effect of the control (agonist alone)
67
is IC50 affected by a change in the agonist conc?
yes
68
What is selectivity?
the relative potency or affinity at one receptor compared with another
69
what is meant by competitive antagonism being surmountable?
it can be overcome/defeated
70
what's the efficacy of a full agonist?
maximum
71
how does a full and partial agonist's max concentration compare?
partial agonists have a lower max concentration than full agonist
72
what's the efficacy of a full antagonist?
0 efficacy
73
what is efficacy?
the effectiveness of a drug
74
why do full antagonists have 0 efficacy?
the block the activation of receptor- don't cause any effect on receptor
75
what is required for a receptor response? (2)
efficacy and affinity
76
do full agonists have efficacy and affinity?
yes- both
77
do partial agonists have efficacy and affinity?
affinity and some efficacy
78
do full antagonists have efficacy and affinity?
affinity and no efficacy
79
how can efficacy be measured?
functional assay
80
what is tone?
the basal activity of a receptor (small ongoing level of activity- activates itself)
81
what is the receptor a dynamic equilibrium between?
active and inactive
82
can antagonists affect tone? how?
yes
| by antagonising endogenous mediators, therefore reducing tone
83
What is non-competitive antagonism also known as?
Allosteric antagonism
84
what is non-competitive antagonism?
when the antagonist binds to another site (than the agonist site) to reduce maximum effect
85
are non-competitive antagonists affected by agonist concentration?
no- because they bind to a different site
86
what's uncompetitive antagonism ?
```
the antagonist also binds to a different site to the agonist
use dependent (work better at a high concentration of agonist as they need the receptor to be activated to work
e.g. a drug that binds inside the mouth of open ion channels and physically plugs them
```
87
what are physiological antagonists also known as?
functional antagonists
88
what are functional/physiological antagonists?
2 agonists that act on different receptors in the same cell type of in different cells in the same system
the total effect= the sum of the 2 activities
89
give 2 examples of 2 functional antagonists
Salbutamol and Methacholine
| Pilocarpine and phenylepherine
90
What do salbutamol and methacholine do?
Salbutamol is an agonist at beta adrenoreceptors in bronchial smooth muscle and activate receptors so the muscle relaxes and the airways dilate
Methacholine is an agonist at muscarinic acetylcholine receptors, causing the muscle to constrict
they counteract each other
91
What do Pilocarpine and Phenylephrine do?
Pilocarpine is a muscarinic acetylcholine receptor agonist- causes pupil constriction
Phenylephrine is an adrenoreceptor agonist- causes pupil dilation
they counteract each other
92
do antagonists have potency?
yes
93
Non-competitive antagonists decrease the apparent efficacy of agonists- true or false?
true (reduces the maximum effect the agonist can produce)
94
Non-competitive antagonists increase the apparent EC50 of agonists- true or false?
false (does not alter the affinity or potency of the agonist- it always has the potential to cause the same max. effect)
95
can a competitive antagonist permanently bind?
no
