Drug Development

Question 1

Outline the traditional route of drug development

Answer 1

A compound is found to have a physiological effect (eg a plant) and the molecular target is derived from this

Question 2

Outline the modern route of drug development

Answer 2

A molecular target exists (eg enzyme) and a complementary compound is designed. The physiological effects are then analysed.

Question 3

How does asparin provide a physiological affect?

Answer 3

Asparin acetylates a serine residue on cyclooxygenase, preventing the substrate from reaching the active site

Question 4

What process is being blocked by asparin?

Answer 4

Prostaglandin synthesis

Question 5

What features of chirality are important to consider when designing a drug candidate?

Answer 5

a. will one chirality be more effective
b. will the body alter the chirality of the drug candidate?
c. will one chirality have a detrimental affect

Question 6

what is the difference between enantiomers and diastereoisomers?

Answer 6

enantiomers are non identical mirror images, all of which are chiral molecules (optically active)
diastereoisomers are not mirror images and are not necessarily chiral. Cis/Trans isomerisation

Question 7

What factors determine L/D chirality?

Answer 7

The relative position of substituents to a reference compound (need a reference compound to be useful)

Question 8

What factors determine +/- chirality?

Answer 8

The rotation of the plane of polarized light. (+ is clockwise)

Question 9

What factors determine R/S chirality?

Answer 9

The absolute configuration around the chiral centre

Question 10

What is the first rule when give R/S chiral compounds priority?

Answer 10

The atomic number of the attached compounds to the chiral carbon. The lowest atomic number is given the least priority

Question 11

If the chiral carbon has one lone pair and one hydrogen bound (and two further groups) which will receive the lowest priority?

Answer 11

the lone pair

Question 12

what is Ec50?

Answer 12

this is the concentration of ligand required to get a 50% biological response from your drug candidate

Question 13

what is Ic50?

Answer 13

Ic50 is the concentration of inhibitor required to decrease target enzyme activity by 50%

Question 14

Which part of ADME does Lipinskis rule of five apply to?

Answer 14

absorption

Question 15

If a compound has a molecular weight of 700, partition coefficient of 2 and 7 H bond donor atoms, will it be well absorbed?

Answer 15

No, this molecule will have poor absorption according to lipinskis rule of 5

Question 16

What is the partition coefficient?

Answer 16

ratio of how well a molecule dissolves in organic solvent vs water. (this is a direct correlation to how well a molecule will dissolve in a biological membrane)

Question 17

If a compound is not soluble in the bloodstream, how will it be transported?

Answer 17

It will be association with HSA - human serum albumin

Question 18

What structural feature of HSA makes it appropriate for its role in drug delivery?

Answer 18

It has an alpha helical structure which has pockets to hold hydrophobic residues

Question 19

What are the two steps of metabolism of xenobiotic compounds?

Answer 19

1. oxidation 2. conjugation

Question 20

What is the purpose of oxidation of foreign molecules?

Answer 20

Oxidation marks the compound as xenobiotic.

Question 21

What enzyme catalyses the oxidation of iboprufen?

Answer 21

Cytochrome p450 catalyses the hydroxylation reaction in the liver

Question 22

What else is require for the oxidation of iboprufen in the body, other than the enzyme?

Answer 22

NADPH and 02

Question 23

Despite metabolism being the bodily process used to discard of the xenobiotic compound, what affect might the conjugation of a foreign body have?

Answer 23

Conjugation can often make the conjugate molecule more active than the drug before conjugation as they are hydrophilic, making the drug more soluble.

Question 24

Briefly describe Erythrocytic Cycling

Answer 24

Molecules which are too large to be filtered through the kidneys will be actively transported in bile to the intestine. Further metabolism will then occur either turning the compound into stool or it can be reabsorbed into circulation via the liver

Question 25

Which compounds will and will not be filtered out by the kidneys in excretion?

Answer 25

Molecules smaller than 60KDa will be filtered out by the kidneys, molecules associated with HSA will not be filtered out (HSA - 65KDa)

Question 26

How can drug toxicity limit the effectiveness of a drug?

Answer 26

The drug could modulate the target too effectively, the drug might have off target effects, the drug might have toxic metabolic by-products.