drug development Flashcards
why is ACE considered a good drug target
- it selectively binds to angiotensin I
- it is bound to the membranes of endothelial cells and is abundant in the lungs which has a large surface area of vascular endothelium making it accessible
- present in other vascular tissues all of which are well perfused
ACE as a binding site
is a zinc metalloprotease and it contains subsite pockets in the active site where the amino acid side chains of angiotensin I fit via complementary interactions
zinc ion in ACE binding site
allows co-ordination of carbonyl groups in peptide bonds to be hydrolysed by polarising it and making it more susceptible to hydrolysis
ACE subsite pockets and their targets
- S1 can bind aromatic groups
- S2’ can bind aliphatic groups
- S2’ can also bind a carboxylate group through a basic side chain in the pocket as carboxylic acid is negatively charged and will bind to amino acids on enzyme
- S1’ can bind aromatic/aliphatic groups
- zinc ion can bind electron rich /negatively charged groups
protein targets
are stereospecific and switching chirality can affect the potency of the drug
stripped bond indicates
chemical group is extending behind
bold bond indicates
chemical group is protruding infront
captopril
dose: 25-50 mg twice/three times daily
logP: 0.62 (lipophilic)
half-life: 2 hours (high dose frequency to accommodate short half-life)
side effects: rash and loss of taste (associated with thiol group)
enalaprilat
- active drug
- poor absorption (logP -0.5)
- good pharmacodynamic activity (carboxylic acid)
enalapril pharmacodynamic
- inactive drug (prodrug)
- good absorption (logP 0.7)
- poor pharmacodynamic activity (ester group too big to fit inside active site pocket)
- liver esterase enzymes hydrolyse enalapril to enalaprilat
enalapril PJ parameters
dose: 2.5 mg once daily
logP: 0.7
half-life: 12 hours
carboxylic acid forms sodium salt
