Key Concepts in Drug Activity

Question 1

What are the types of non-covalent interaction that can influence drug-receptor binding?

Answer 1

Salt bridges, hydrogen bonding, hydrophobic effects, van der Waals forces, aromatic interactions and cation-pi interactions

Question 2

What is IC50?

Answer 2

Concentration of a drug that produces half maximal inhibition - inhibitory concentration.

Question 3

What is EC50?

Answer 3

Concentration of a drug that produces a half maximal response - effective concentration.

Question 4

How can you estimate IC50 and EC50 values from experimental data and what data is required?

Answer 4

Dose-response curves, % response vs concentration (generally semi-log)

Question 5

What is efficacy?

Answer 5

= Instrinsic activity, alpha. Magnitude of the effect produced by a bound drug. Alpha = 1 = maximal response. Mix of alpha and dissociation constant affect potency of a drug.

Question 6

What is an agonist?

Answer 6

Compound that produces the same response as the normal ligand for a receptor. Full/partial refers to alpha values.

Question 7

What is an antagonist?

Answer 7

Inhibits the response of a receptor to its normal ligand or an agonist.

Question 8

What is an inverse agonist?

Answer 8

Produces opposite effect to the normal ligand or agonist, requires receptor to have baseline activity.

Question 9

What is seen in a dose-response curve for a full agonist?

Answer 9

S-shaped curve with alpha = 1.

Question 10

What is seen in a dose-response curve for a partial agonist?

Answer 10

S-shaped curve with 0 < alpha < 1

Question 11

What is seen in a dose-response curve for an inverse agonist?

Answer 11

S-shaped curve into negative % response.

Question 12

What is seen in a dose-response curve for a competitive antagonist?

Answer 12

Measure % response against log [agonist] with multiple lines representing increase conc. of antagonist. Same maxima for each S-shaped curve, increasing concentration of antagonist will shift the midpoint of the curve to increased levels of agonist. At high concentrations of agonist, antagonist is outcompeted.

Question 13

What is seen in a dose-response curve for a non-competitive antagonist?

Answer 13

Measure % response against log[agonist] with multiple lines representing increase conc. of antagonist. Same mid-point for each curve, but decreased maxima, fewer agonist-receptor bindings are possible to smaller response.

Question 14

What reactions occur during phase I metabolism?

Answer 14

Changes to functional groups of a molecule to form more polar groups and improve solubility, removal of reactive electrophiles.

Question 15

What reactions occur during phase II metabolism?

Answer 15

Conjugation of water-soluble component such as glutathione, bioconjugation.

Question 16

What do DMPK and ADME(T) stand for?

Answer 16

DMPK = drug metabolism and pharmacokinetics
ADME(T) = absorption, distribution, metabolism, excretion, (toxicity).

Question 17

What factors need to be considered for absorption?

Answer 17

Solubility, acid stability (stomach pH 2, small intestine pH 7), permeability (transcellular/paracellular), metabolism.

Question 18

What is a common drug interaction that can arise due to metabolic interactions?

Answer 18

Some drugs inhibit CYP (cytochrome P450). Other drugs metabolic pathways will involve CYP. Inhibition of CYP metabolic pathways could allow build up of other drugs, potentially leading to toxic levels.

Question 19

What is the octanol-water partition coefficient?

Answer 19

Measure of compound solubility.
log P = log (drug(oct)/drug(water))

Question 20

What is the distribution coefficient?

Answer 20

Measure of compound solubility taking speciation effects into account. pH-dependent value.

Question 21

What do the partition and distribution coefficients indicate?

Answer 21

Give an idea of bioavailability of drug, with optimum value for traversing cell membranes. Too hydrophobic, move to octanol - insoluble. Too hydrophilic, move to water - won’t pass through blood-brain barrier.

Question 22

What makes a good drug?

Answer 22

Effective (good affinity for target, high intrinsic activity and good bioavailability), safe (predictable bioavailability and metabolism), selective (limited side effects from off-target activity)

Question 23

What is Lipinski’s rule of five?

Answer 23

Molecular weight < 500, no more than 5 H-bond donor groups, no more than 10 H-bond acceptor groups, calculated logP < 5. Describes criteria satisfied by most successful small organic drugs.