Lec 4

Question 1

What is LD50?

Answer 1

lethal dose - dose required to kill 50% of test animal subjects (can test toxins, the actual drug)

Question 2

Give the equation for the Therapeutic index

Answer 2

TI = LD50 / ED50

Question 3

Do we want a high/low Therapeutic Index and why?

Answer 3

high - therefore we will have a high lethal dose (therefore lots required to kill the animal) and low dose required to elicit a response (ED50)

Question 4

What does a low TI mean in terms of the health of the organism?

Answer 4

a low TI means that a high vol of the drug will have to be administered meaning that it could be toxic to the body and close to killing

Question 5

Give the 3 main effects that substituting C-H with C-F will give you

Answer 5

• increased bioavailiabilty
• increased binding to targets and reduce binding to other targets
• increase lipophillicity

Question 6

Why is F a H mimic?

Answer 6

• C-H and C-F bond lenghts are v similiar
• the VDW radius of each atom is v similar

Question 7

What occurs when F is added to a C group adjacent to a carboxylic acid group and why? eg

FCH2COOH

Answer 7

• pKa of COOH group is reduced making it more likely to act as an acid
• F is v electronegative
• however this has no biological effect because we still get ionisation

Question 8

1. What occurs when an F is added to a C group adjacent to an amine? Draw the deprotonation reaction @ eqm
2. What is the overall effect of this?

eg FCH2NH3+

Answer 8

1. reduces the basicity of the compound (and the pKa)
2. therefore deprotonated state is more likely therefore is more lipophillic and is therefore more bioavailable (improved distribution)

Question 9

Why does this fluorinated compound not show an increase in lipophillicity?

Answer 9

• more aqueous in water
• F group increases the overall polarity of the molecule leading to a gain in solvation energy in the aqueous solution
• stronger H bonds can also be made to water from the O

Question 10

How does fluoridation affect the metabolism of a compound?

Answer 10

• because the C-F bond is much stronger than C-H the cytochrome P450 isozyme cannot catalyse the oxidation reaction therefore the drug will not be metabolised as much
• increased bioavailability

Question 12

how does fluoridation increase the distribution of the drug in terms of the serum carrier proteins?

Answer 12

increases the binding of the drug to HSA therefore increases distribution

Question 13

In what situation is a compromise reached when fluoridating the molecule?

Answer 13

• serotonin receptor ligand
• protonated form binds the receptor most effectively
• fluoridation results in reduction in pKa of amide N and therefore increases its bioavailability but also results in the deprotonated form being prominent so compromise is reached

Question 14

Give the 3 main methods of drug discovery and give an example for each.

Answer 14

• serendipity - penicillin
• screening - aspirin
• design - crixivan

Question 15

Describe penicillin’s mode of action

Answer 15

inhibits the transpeptidase involved in peptidoglcyan synthesis

Question 16

1. What is Crixivan effective against?
2. describe its structure
3. state how this structure came about

Answer 16

1. HIV protease
2. 2 separate inhibitor molecules, differing in their activities and solubilites, linked together by an OH group
3. X ray crystallography of HIV protease identified its target site and drug structure was based on this knowledge

Question 17

What is the purpose of the OH group within the Crixivan structure

Answer 17

mimics the transition state/intermediates seen in the mechanism of the Asp protease (HIV protease)

Question 18

Give the 4 stages in the production/design of a new drug

Answer 18

1. identification of a target
2. screening for the lead compound
3. modifications/improving bioavailability (ADME)
4. clinical trials

Question 19

How are potential targets for therapy identified in organisms?

Answer 19

• prokaryotes; gene knockouts etc - does this lead to the diseased state still?
• genomics
• humans; around 800 GPCR targets, 500 genes encoding kinases, are some genes only expressed in diseased state?, any post translational modifications on diseased proteins?

Question 20

Give an example of where genetic differences can affect drug efficacy

Answer 20

• metoprolol - B blocker against a receptor involved in hypertension - aimed to reduce blood pressure
• having most common genotype SR/SR allows the drug to work at its highest efficency and reduce blood pressure
• however having a GR/SG genotype means that the drug has minimum effectiveness

Question 21

1. How can we identify a lead compound?
2. What are the main competitors of drugs in the body?

Answer 21

1. look at transition states, substrates, mimics that fit AS all in a hope to create an effective drug - can have ligand/receptor targets
2. the natural substrate is the main competitor

Question 22

What is combinatorial chemistry?

Answer 22

combining various molecules etc together w/ various bond to create a wide range of chemicals

all of which can be assayed and screened for their effectiveness against a specific target

however not all products possible can be made/screened because there are so many

Question 23

How many phases to a clinical trial are they and what are the general purposes of performing clinical trials?

Answer 23

4 phases

all designed to test the efficacy, safety and any related side effects of a drug