D3 - agonism dynamics Flashcards
Pharmacodynamics
how drugs can bind to a drug target and how this produces a therapeutic response
- Impact of drug binding on the target - Impact of drug binding on cell response
How drugs bind to drug targets
- 99% of drugs used bind to drug target
○ Typically reversible - can dissociate again- Receptors
○ Recognise presence of hormone, drug, neurotransmitter, mediator, drug
○ Transduce binding signal to downstream signalling pathway to produce a change in cellular activity
- Receptors
B1 adrenoceptors
○ In cell membrane of cardiac cells
○ Recognise adrenaline and noradrenaline
○ Changes intracellular calcium levels
○ Increase heart rate and contractility
Receptors
- Receptors are proteins
○ Large
○ Typically >300 amino acids in length that have small cavities for drug binding
○ Have small cavities for drug binding - binding site
○ Arrangement of amino acids and functional groups
○ Binding site and drug have
§ complimentary 3 dimensional shapes
§ chemical forces of attraction
□ Typically weak chemical forces - hydrogen bonds, ionic bonds, van der walls
□ Covalent bonds rarely involved
○ When a drug comes into close proximity to the binding site - drug becomes activated because of existence of chemical forces of attraction between it and the binding site
○ Drug will bind to binding site depending on
§ 3 dimensional fit
§ existence of chemical forces - hydrogen bonds, ionic bonds, van der waals forces
○ Binding reflects affinity
Affinity
○ Tendency of a drug to bind to it’s drug target
○ Affinity depends upon
§ complimentary chemical forces
§ Complimentary three dimensional shapes
○ Without affinity, drugs don’t bind - don’t work
Strength of chemical forces varies based on
- Type of bond involved in binding
○ Van der walls - weak
○ Hydrogen - slightly stronger
○ Ionic bonds - stronger still
○ All much weaker than covalent bonds- Distance between receptor and drug
○ Inverse relationship between distance and strength of binding
§ most acute for van der walls forces
□ Strength of wan der walls forces dissipates quickly as distance is increased
○ Less acute for ionic bonds
§ Still exists inverse relationship of distance and strength
○ Good 3 dimensional fit will minimise the distance between the drug and it’s target - Total number of bonds involved
○ More bonds -> stronger the binding
- Distance between receptor and drug
Affinity enables drug binding
How much drug binding depends upon drug concentration
- Binding is reversible
- Drug-drug target complex can dissociate again
- Equilibrium
- Law of mass action
○ As the concentration of drug is increased, equilibrium is forced to the right
§ Greater fraction of targets is bound by the drug
○ Fraction of target bound by the drug is dependant on
§ concentration of drug
§ affinity of drug for the receptor - Ka value
- Drug/(drug + Ka) = fraction of target bound by drug
- Law of mass action
○ As the concentration of drug is increased, equilibrium is forced to the right
§ Greater fraction of targets is bound by the drug
○ Fraction of target bound by the drug is dependant on
§ concentration of drug
§ affinity of drug for the receptor - Ka value
Ka value
- The concentration of drug occupying 50% of receptors
- Measure of affinity of the drug for the receptor
- Equilibrium dissociation constant
- Measure of affinity of the drug for the drug target
- Measure of the concentration of the drug at which 50% of the drug target is bound
- Inverse relationship between the size of the Ka and the affinity
○ Low Ka value indicates high affinity
○ Only high affinity drugs bind at low concentrations - Constant value for a given drug/drug target pair
○ Relative term - will be different with different drug pairs
○ Difference in Ka value can explain
§ Why drugs vary in potency
§ Why drugs have selectivity
Inverse relationship between the size of the Ka and the affinity
○ Low Ka value indicates high affinity
○ Only high affinity drugs bind at low concentrations
- Constant value for a given drug/drug target pair
○ Relative term - will be different with different drug pairs
○ Difference in Ka value can explain
§ Why drugs vary in potency
§ Why drugs have selectivity
Saturation
- Almost all receptors are bound by the drug
- Increasing concentration of the drug wont cause significant increase in the fraction of receptors bound by the drug
Drugs that activate drug targets
○ agonists
○ Eg. Adrenaline binds and activates beta-1 adrenoceptor causing increase in intracellular calcium levels and increase in heart rate and contractility
Agonist binding
- When an agonist is in the vicinity of the receptor it can bind to the site and induce a conformational change affecting the rest of the receptor
- Activation of the receptor so that it can bind to and activate down stream signalling pathways
- Agonists have affinity enable binding to receptor - also posses efficacy
○ Efficacy
Ability to activate receptor
Efficacy at G protein coupled receptors - ability to activate the receptor
- B2 receptor is a G-protein coupled receptor
○ A single protein that fold to form 7 transmembrane regions spanning the cell membrane creating a barrel structure in the cell membrane
○ The binding site is a third of the way down the barrel-like structure
○ One of the transmembrane domain helixes moves (number 6) to generate a binding pocket for the G protein
○ When activated - a binding pocket is created which can be occupied by a g protein
High efficacy agonists
- Cause a high level of receptor activation
* Called full agonists
