drug design and development

Question 1

what is a drug?

Answer 1

a chemical substance of known structure which produces a biological effect when administered

Question 2

what are the requirements for a drug?

Answer 2

• soluble in water and fat
• cell penetrable
• potent
• selective

Question 3

what are Lipinski’s rule of 5?

Answer 3

a compound is more likely to be absorbed if:

1) molecular weight below 500g/mol
2) low lipophilicity logP<5
3) fewer than five H-bond donor atoms
4) fewer than 10 H-bond acceptor atoms
5) level of ionisation compared to environment

Question 4

what is the druggable proteome?

Answer 4

the fraction of proteins which have the ability to bind a small molecule with the required affinity and appropriate chemical properties, and at the same time are potential drug targets that are linked to a disease

Question 5

outline the drug development process

Answer 5

1) drug discovery: during which candidate molecules are chosen on the basis of their pharmacological properties
2) pre-clinical development: during which a wide range of non-human studies including toxicity testing, pharmacokinetic analysis and formulation are performed
3) clinical development: during which the selected compound is tested for efficacy, side effects and potential dangers

Question 6

how are targets identified in infectious disease?

Answer 6

target a protein known for growth/reproduction, must be unique to host or have detailed structural differences. perform genome analysis

Question 7

how are targets identified in genetic disease?

Answer 7

target is endogenous, extensive knowledge of cellular, molecular, and biochemical details of the disease are required. genome analysis required

Question 8

explain how a target in E.coli could be found

Answer 8

sequence: model E.coli genome has 4289 genes
spectrum: 246 genes conserved with humans
comparison with human sequences: 68 not the same as found in humans
loss of function tests: identifes 18 essential genes, 16 non-essential, 34 unknown

Question 9

explain how a target for malaria could be found

Answer 9

sequence: genome has 5,300 genes in 14 chromosomes
function of proteins (knockout): 2/3 genes responsible for growth, identifies essential parasite genes and pathways for drug-target prioritisation
comparison with human proteins: 60% unique to parasite