Lecture 6

Question 1

what is a drug?

Answer 1

any substance which when absorbed into a living organism may modify one or more of its functions.

Question 2

interactions between the drug molecule and human body are…

Answer 2

-multifaced
- difficult to model with high accuracy

Question 3

what is the purpose of lupinski rule of 5?

Answer 3

a set of empirical rules to recognise essential features in orally administrated drugs

Question 4

what are Lipinski’s rule of 5?

Answer 4

• molecular weight <500amu (atomic mass units)
• logP <5
• <5 H bond doners (sum of NH and OH)
• <10 H bond acceptors (sum of N and O)
• <10 rotational bonds (otherwise absorption and bioavailability are likely to be poor)

Question 5

what is one of the most important factors affecting biological activity?

Answer 5

molecular size

Question 6

measuring molecular size of a drug molecule can be hard. what can the molecular size be indicated by?

Answer 6

the molecular weight of drug molecules

Question 7

an indication of molecular size can also be indicated using what?

Answer 7

• electron density
• polar surface area
• van der waals surface
• molecular refractivity

Question 8

partition coefficient P is defined as…

Answer 8

P = [x] octanol / [x] aqeous

x = drug

Question 9

what is logP a measurement of?

Answer 9

a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation.

Question 10

why is 1-octanol the most frequently used lipid phase in pharmaceutical research?

Answer 10

• it has a polar and non-polar region
• p o/w is fairly easy to measure
• p o/w often correlates well with many biological properties
• it can be predicted fairly accurately using computational models.

Question 11

what are the majority of drug molecules?

Answer 11

weak acids or bases (sometimes both)

Question 12

the extent of drug ionisation on the basis of the pH of the solution in which the drug is found can be calculated using…

Answer 12

Henderson-Hasselbalch equation

Question 13

what does it mean for a compounds logP if the compound can ionise?

Answer 13

its logP will be pH dependant.

Question 14

what is the distribution coefficient logD?

Answer 14

-is the effective lipophilicity of a compound at a given pH
- is a function of both the lipophilicity of the un-ionised compound and the degree of ionisation

Question 15

favourable outcomes logP affects?

Answer 15

• increases binding to enzyme/receptor
• increases absorption through membrane

Question 16

undesirable outcomes of logP?

Answer 16

• decreases aqueous solubility
• increases binding to p450 metabolizing enzymes
• increases binding to blood/tissue proteins meaning less drug free to act
• increases binding to hERG heart ion channel meaning a cardiotoxicity risk.

Question 17

intermolecular H- bonding between small molecules in diluted aqueous solutions.

Answer 17

virtually non-existent

Question 18

intramolecular H-bonding in diluted aqeous solutions

Answer 18

more readily formed because they are entropically more favourable as between same molecule rather than 2 different molecules.

Question 19

how are most oral drugs absorbed?

Answer 19

through the gut wall by passive transcellular absorption

Question 20

De-solvation and formation of a neutral molecule is unfavourable if…

Answer 20

the compound forms too many hydrogen or ionic bonds with water

Question 21

Too many hydrogen bond donors or acceptors are undesirable because…

Answer 21

the drug will not easily get from the gut into the blood stream.

(exception = carbohydrates which have special mechanism)

Question 22

what is a rotational bond?

Answer 22

any single bond which is not in a ring and bound to a nonterminal heavy (non-hydrogen) atom.

excluding amide C-N bonds due to their high rotational energy barrier.

Question 23

what does the number of rotational bonds influence?

Answer 23

-bioavailability
-binding potency

Question 24

rotational bonds on entropy.

Answer 24

A molecule will have to adopt a fixed conformation to bind to a macromolecule. This involves a loss in entropy. More rigid molecules (aromatics or conformationally constrained moieties) will pay a lower entropy penalty.

Question 25

substitution of more flexible functional groups than ridged ones…

Answer 25

can potentially restrict the molecule into the wrong conformation, resulting in a loss of biological activity.