Drug Discovery Flashcards
What possible drug targets are there?
Enzymes
GPCRs
Receptors
Ion channels
Solute carriers
How does Aspirin work as a drug?
Acetylates a Ser residue in the cyclooxygenase of prostaglandin H2 synthase
Binds to a hydrophobic pocket
What is reduced when prostaglandin levels are reduced?
Inflammation
Fever
Pain
Blood clotting
What is IC50?
Concentration of inhibitor to elicit 50% decrease in activity
What are lipinskis rules.of 5?
Poor absorption when:
Molecular weight > 500
Partition coefficient > 5
H-bond donors > 5
H-bond acceptors > 10
What is a partition coeffient?
Tendency for a molecule to dissolve in membranes.
Correlates.with ability.to dissolve organic solvents
What phase I metabolism can happen to drugs?
Oxidation
Conjugation
What happens to ibuprofen in the liver?
Oxidised by cytochrome P450
What is the key feature of penicillin?
ẞ- lactam ring.
Inhibits transpeptidase of peptidoglycan synthesis
What factors are involved in drug efficacy?
Absorption
Distribution
Metabolism
Excretion
What sort of drugs to kidneys absorb?
Glomeruli filters blood
Compounds less than <60kDa
Glucose, nucleotides, water and drugs are reabsorbed into blood
How can rate of excretion of a drug be reduced?
Enterohepatic cycling: Compounds are actively transported into bile then the intestine. Further metabolism occurs or the drug is reabsorbed
How is drug toxicity measured?
LD50 or EC50
How can drug toxicity affect the target?
The target can be modulated too effectively
Off target effects on the same or different family
How does substitution C-H for C-F affect a drug?
Increased bioavailability
Increased metabolic stability
Increased lipophilicity unless there is a C-O near the F
Why may fluorinating a drug decrease the lipophilicity?
If F is near a C-O, the F has an electron withdrawing effect. This makes the compound polar and soluble in water
How can fluorination affect metabolism of a drug?
C-F is stronger than C-H, making oxidation by cytochrome P450 more difficult
How can chirality affect binding
Switching chirality of a compound can prevent it binding to the active site as groups are in different positions
What sort of drugs can target enzymes?
Substrate mimics
Transition state mimic
What sort of drugs can target receptors?
Natural ligand mimic
Monoclonal antibody
How do rhinovirus inhibitors work?
Supress symptoms of a peptide mimic
Briefly describe Sars-COV2 viral proteases
Cleaves after Gln. The intermediate has Cys145 covalently bound to the drug
