Drug Discovery

Question 1

What possible drug targets are there?

Answer 1

Enzymes
GPCRs
Receptors
Ion channels
Solute carriers

Question 2

How does Aspirin work as a drug?

Answer 2

Acetylates a Ser residue in the cyclooxygenase of prostaglandin H2 synthase
Binds to a hydrophobic pocket

Question 3

What is reduced when prostaglandin levels are reduced?

Answer 3

Inflammation
Fever
Pain
Blood clotting

Question 4

What is IC50?

Answer 4

Concentration of inhibitor to elicit 50% decrease in activity

Question 5

What are lipinskis rules.of 5?

Answer 5

Poor absorption when:
Molecular weight > 500
Partition coefficient > 5
H-bond donors > 5
H-bond acceptors > 10

Question 6

What is a partition coeffient?

Answer 6

Tendency for a molecule to dissolve in membranes.
Correlates.with ability.to dissolve organic solvents

Question 7

What phase I metabolism can happen to drugs?

Answer 7

Oxidation
Conjugation

Question 8

What happens to ibuprofen in the liver?

Answer 8

Oxidised by cytochrome P450

Question 9

What is the key feature of penicillin?

Answer 9

ẞ- lactam ring.
Inhibits transpeptidase of peptidoglycan synthesis

Question 10

What factors are involved in drug efficacy?

Answer 10

Absorption
Distribution
Metabolism
Excretion

Question 11

What sort of drugs to kidneys absorb?

Answer 11

Glomeruli filters blood
Compounds less than <60kDa
Glucose, nucleotides, water and drugs are reabsorbed into blood

Question 12

How can rate of excretion of a drug be reduced?

Answer 12

Enterohepatic cycling: Compounds are actively transported into bile then the intestine. Further metabolism occurs or the drug is reabsorbed

Question 13

How is drug toxicity measured?

Answer 13

LD50 or EC50

Question 14

How can drug toxicity affect the target?

Answer 14

The target can be modulated too effectively
Off target effects on the same or different family

Question 15

How does substitution C-H for C-F affect a drug?

Answer 15

Increased bioavailability
Increased metabolic stability
Increased lipophilicity unless there is a C-O near the F

Question 16

Why may fluorinating a drug decrease the lipophilicity?

Answer 16

If F is near a C-O, the F has an electron withdrawing effect. This makes the compound polar and soluble in water

Question 17

How can fluorination affect metabolism of a drug?

Answer 17

C-F is stronger than C-H, making oxidation by cytochrome P450 more difficult

Question 18

How can chirality affect binding

Answer 18

Switching chirality of a compound can prevent it binding to the active site as groups are in different positions

Question 19

What sort of drugs can target enzymes?

Answer 19

Substrate mimics
Transition state mimic

Question 20

What sort of drugs can target receptors?

Answer 20

Natural ligand mimic
Monoclonal antibody

Question 21

How do rhinovirus inhibitors work?

Answer 21

Supress symptoms of a peptide mimic

Question 22

Briefly describe Sars-COV2 viral proteases

Answer 22

Cleaves after Gln. The intermediate has Cys145 covalently bound to the drug