Drug Discovery

Question 1

Three phases of drug action

Answer 1

1. Pharmaceutical: initial phase of drug in body after administration where formulation breaks apart and the active ingredient dissolves
2. Pharmacokinetic: deals with kinetics of drug absorption, distribution, and elimination. Is the study of the body’s actions on the drug
3. Pharmacodynamic: Study of drug’s actions on the body

Question 2

Pharmacokinetics

Answer 2

study of ADME/T (Absorption, Distribution, Metabolism and Excretion)

Question 3

Main 2 considerations in drug design

Answer 3

1. Pharmacokinetics: drug should have good ADME/T profile
2. Pharmacodynamics: drug should have high potency and specificity with intended target

Question 4

Lipinski ‘rule of 5’

Answer 4

1. MW =<500Da (optimally ~350)
2. no. of H bond acceptors =<10 (optimally ~5)
3. no. of H bond donors =<5 (optimally ~2)
4. no. of rotatable bonds =<10
5. -2 < log P < 5 (optimally 0.5-3)

Question 5

Lipinski RO5 explained

Answer 5

MW: better absorption via membrane permeability
Hydrogen bonds: regulate drug polarity & ensure it can pass through cell membrane
Rotatable bonds: for a more rigid conformation
Log P: determines solubility of a drug, and therefore the absorption, distribution and excretion

Question 6

Pharmacokinetic ADME

Answer 6

Absorption: transfer of drug from site of administration to blood circulation
Distribution: transfer of drug from general circulation to different organs of the body
elimination: removal of drug from body, involves metabolism and excretion

Question 7

Drug absorption

Answer 7

occurs at GI, most activity at small intestines

Transcellular passive diffusion as main pathway of absorption

For diffusion through lipid bilayer:
- low MW (small in size)
- hydrophobic

Pathway:
Intestinal lumen -> Intestinal wall -> blood -> venules -> mesenteric vein -> hepatic portal vein

Question 8

Factors affecting extent of distribution/apparent volume of distribution

Answer 8

1. plasma protein binding (acidic drug binds to albumin, basic to globulin)
2. Tissue localization (binding to tissue components)

Question 9

Drug property on Vd (vol of distribution)

Answer 9

1. Acidic drugs are bound to plasma protein, not lipophilic enough to distribute intracellularly (small volume of distribution)
2. Basic drugs are highly distributed in tissues: low plasma concentration (large volume of distribution)

Question 10

Drug metabolism (elimination)

Answer 10

Liver converts active drug into it’s highly-water soluble inactive metabolites for easy removal via urine

Question 11

Drug excretion

Answer 11

Kidney filters the blood and removes waste products and excess organic molecules

Question 12

Plasma clearance (CL of drug)

Answer 12

deteremined by elimination process ( metabolism and excretion), refers to how easy it is to clear drug from the body

• Affects drug’s half life
• CL is a constant
• vol of plasma cleared of the drug per time unit

Question 13

Selected drug examples

Answer 13

1. penicillin
2. vancomycin
3. artemisinin (青蒿)
4. paclitaxel
5. arscenic trioxide
6. retinoic acid

Question 14

penicillin (beta-lactam antibiotics)

Answer 14

produced from mould

basis of antibiotics and vaccinations

inhibit bacterial cell wall synthesis

mimics peptidoglycan transpeptidase and inactivates enzymes

Question 15

vancomycin

Answer 15

glycopeptide antibiotic targeting gram positive bacteria

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