lecture 09

Question 1

what does a drug need to be classed as drug- like

Answer 1

must be selective for targets to avoid adverse effect, have a high affinity for the target, have slow metabolism to allow sustained activity and reduced dosing frequency, no toxic metabolites and good distribution to allow access to target and reduce elimination rate

Question 2

what administration does a chronic disease require and how do we manage this

Answer 2

oral administration: so drug has tobe water soluble, lipophilic to allow it to absorbe from the GI tract and stable within the GI environment

Question 3

why is high potency a good thing

Answer 3

higher potency, lower required dose - so less likelihood of side effects

Question 4

what must a drug have to generate a pharmacodynamic output

Answer 4

functional groups which permenantly engage with amd fit into the target protein to allow emzyme inhibition

Question 5

what must drugs have for ADME

Answer 5

functional groups which allow the right pharmacokinetic profile to enable access to target for a sustained period of time

Question 6

what makes ACE a good drug target

Answer 6

it is accessible as its bound to membranes of endothelial cels and is particularly abundant in the lungs which has a large surface area of endothelium, also its present in other vascular tissues - all of which are well perfused

Question 7

AG1 and AG2 are example of

Answer 7

peptides

Question 8

what amino acid are you breaking off of AG1 to make AG2

Answer 8

Histamine and leucine

Question 9

where does ACE hydrolyse the peptide bond

Answer 9

between Phe and His , at the 2nd peptide bond in from the c terminus

Question 10

how many amino acids in AG1

Answer 10

10

Question 11

name the amino acids at each of the sites of the ACE enzyme and what they can bind

Answer 11

S1- phe ( binds aromatic groups)
S1’ - His ( binds aromatic or aliphatic groups)
S2’ - Leu ( binds aliphatic groups and carboxylate through basic side chain in the extra pocket)
The 4th site is a zinc ion ( binds negatively charged/ electron rich groups)
(‘=prime )

Question 12

what does the zinc ion site in the ace enxyme do

Answer 12

it coordinates the carbonyl of peptide bond which gets hydrolysed - this polarises it and makes it more susceptible to hydrolysis

Question 13

what is the name of the peptide found in snake venom which inhibited ACE but was too toxic

Answer 13

teprotide

Question 14

why was teprotide useful

Answer 14

because it did inhibit ACE, it was just too toxic, so it alloed us to develop other drugs

Question 15

what amino acid in teprotide was the bit useful at inhibiting ACE consistent with other drugs

Answer 15

proline

Question 16

why is succinlproline not good for ACE inhibition

Answer 16

didnt make use of S1 or S1’ sites - so wouldnt have outcompeted the actual substrate

Question 17

what functional groups in an ACE inhibitor theoretically reduce the IC 50

Answer 17

Thiol ( SH) instead of COOH, methyl compared to H and preferrably in the S conformation, and a carboxyl group on the proline

Question 18

what are the issues with a thiol

Answer 18

thiol group was associated with side effects of a rash and loss of taste

Question 19

carboxyalkanolylproline ws improved to make______ by ________

Answer 19

make enalaprilat by adding additional groups that can interact with additional pockets of the ACE binding site ( an aromatic group for the s1 site)

Question 20

what was the problem with enalaprilat

Answer 20

too hydrophilic, so wouldnt absorb as -log p ( lipophilic )

Question 21

how was enalaprilat improved so it could be taken orally

Answer 21

added an ethyl ester ( which is easily broken down by liver esterases) so that enalaprilat would be released once it is in circulation.

Question 22

what kind of drugs are ramapril and enalapril

Answer 22

pro drugs