medicine for cvd Flashcards
How does a drug bind to a target?
- induced fit
- target will change shape to accommodate the molecule
- have binding interactions with the molecule which holds it in place
what is intramolecular bonding ?
Intramolecular bonding
Bonding within the same molecule – including covalent bonding
what is intermolecular bonding?
Intermolecular bonding
Bonding between two neighbouring molecules – Non-covalent
what is lock and key hypothesis?
Rigid structure
Perfect fit to active site
No explanation for multiple substrates
what is Koshland’s theory of induced fit
Substrate not ideal shape for active site
Active site forced to change
Change in shape driven by maximisation of intermolecular binding interactions
Explains how range of substrates tolerated by enzyme or receptor
Note that substrate is not a passive spectator.
Binding interaction must be strong enough to hold substrate but must allow release of products or neurotransmitter
What are the main structural requirements for selective binding to the α1 subunit of L-type calcium channels?
(amlodipine)
Structural requirements, chloro group on the aromatic ring lock the ring perpendicular to the dihydropyridine.
Also worth noting that the terminal amino group is important for formulation and ionic interaction in membranes.
Protonation at physiological pH allows formulation as the maleate salt
explain the structure of the molecule which bind to beta adrenoreceptor when they are an agonist?
Agonists mimic the natural messenger and need to bind to the receptor in such a way to activate it.
Need to consider 3 main points:
Drug must have correct binding groups.
Binding groups must be in the correct position
Drug must be correct size for binding site
explain the structure of the molecule which bind to beta adrenoreceptor when they are an antagonist?
The Antagonist must bind more strongly than the natural messenger, but not activate the receptor. This can be achieved in several ways:
Design a molecule to use the natural binding interactions, that perfectly fits into the active site, and block the required induced fit of the target.
Design a molecule to use alternative binding sites within the target site, to enhance binding affinity, and cause an alternative induced fit that does not activate the receptor.
Why would you give a patient salbutamol to alieve the symptom of bronchospasm due to an overdose of atenolol?
Atenolol is an antagonist for β-adrenergic receptors, whilst salbutamol is a β2-receptor agonist. Bronchospasm due to atenolol is from excessive action on both β1- and β2-receptors. Adding an agonist will return normal levels of activity.
: Why is atenolol an antagonist and salbutamol an agonist for the same receptor?
Size (the agonists are smaller – maximising induced fit)
Similar placement of h-bonding groups – same binding interactions but (1) means that these are in a slightly different position for atenolol, reducing induced fit
Tert-butyl group on salbutamol could be advantageous
How does the design of an agonist result in agonistic behaviour?
Answer: Correct size of molecule (1 mark), with the correct binding interactions (1 mark), in the correct orientation (1 mark) will result in similar binding to the natural substrate.
If the binding is similar it will result in the correct induced fit (1 mark), and therefore the receptor will be activated in the same way as the natural substrate (1 mark).
hydrogen bond acceptors :
All groups containing a heteroatom (O or N) should be circled
