Lecture 6: Drug development in Cardiovascular disease Flashcards
What are the properties that make a drug ‘drug like’
- Selective for the target to avoid adverse effects
- High affinity for the target
- Chronic disease requires oral administration: Water solubility to allow for oral formulation (chronic disease treatment), Lipophilicity to allow absorption from the gastro-intestinal tract, Stability within the gastro-intestinal environment
- Slow (hepatic) metabolism to allow for sustained activity and reduced dosing frequency
- No toxic metabolites
- Bodily distrinution to fascilitate access to the target and reduce eliminiation rate
How does the angiotensin cascade reduce blood pressure?
Reducing the amount of angiotensin II in the circulation - inhibiting angiotensin converting enzyme could achieve this
What makes ACE a good drug targer?
- Its an enzyme that selectively binds a substrate (angiotensin I) and enzymes can be inhibited
- Has a 3D active site that recognises a specific substrate, so building molecules to fit the site is possible
- The enzyme is accessible - bound to membranes of endothelial cells and is particularly abundant in the lung, which has a bast surface area of vascular endothelium
- Its also present in other vascular tissues (heart, striated muscle, kidney) all of which are well perfused
How does ACE convert angiotensin I to angiotensin II?
ACE hydrolyses peptide (amide) bond specifically between Phe and His on angiotensin I.
What is the end of a peptide chain called?
C terminus
What is the start of a peptide chain called?
N terminus
What does ACE have that helps amino acid side chains of angiotensin I fit into it?
Subside pockets
What prime pocket does Phe go into in ACE?
S1
What prime pocket does Leucine go into in ACE?
S2
What prime pocket does His go into in ACE?
S1’
What is the function of zinc in ACE?
Zinc ion in ACE active site, co-ordinates carbonyl of peptide bond to be hydrolysed. It polarises it and makes it more susceptible to hydrolysis
What groups does S1 bind to?
Aromatic groups
What groups does S2’ bind to?
Aliphatic groups
What groups does S2’ bind to?
Carboxylate group through an arginine sidechain in the pocket
What groups does S1’ bind to?
Aromatic/ aliphatic groups
What does the zinc ion bind to?
Electron rich/ negatively charged groups
What is a zinc metalloprotease?
Uses zinc in the active site to catalyse the hydrolysis of peptide substrates
What do all peptidases have?
S3/S2/S1/S1’ pockets
What groups does the active site of ACE have?
- Phenol
- Leucine
- His
What groups does the active site of MMP1 have?
- Asp
- Ser
- Pro
What is teprotide?
A nonopeptide isolated from snake venom, was known to be an inhibitor of ACE
What are the disadvantages of peptides as drugs? (3)
- Peptides make poor drugs for oral administration
- Sesceptible to degradation by peptidases in the GIT
- Tend to be hydrophillic which reduces permeability through cell membranes
What is succinyl-L-proline?
Succinic acid combined with proline
What is the potency of succinyl-L-proline?
IC50 = 630
