Drug development

Question 1

What can be used as targets for drugs?

Answer 1

-enzymes
-receptors (GPCRs, nuclear receptors, etc)
-ion channels (volt and lig -gated)
-transporters (solute carriers, etc)

Question 2

What regions do drug candidates tend to have?

Answer 2

-hydrophobic regions (interactions with hydrophobic pockets)
-H-bond donors and acceptors (H-bonds)
-charge carriers (interactions)
-ring structures (pi-pi stacking interactions)

Question 3

drug selectivity to target =

Answer 3

Kd drug binding to other molecules / Kd drug binding to target

Question 4

What is ADME?

Answer 4

a set of characteristics of a drug to check it is suitable for use in human body
Absorption
Distribution
Metabolism
Excretion

Question 5

What effect does fluorination have on a drug’s properties?

Answer 5

-improves bioavailability (by modulating binding to human serum albumin; reducing metabolism due to C-F being stronger bond than C-H)
-alters lipophilicity (usually increases it because F is v. electronegative; except when F added next to O)

N/B: F is a good mimic for H :) (because sim bond length and van der Waals radius!)

Question 6

How does fluorination make drug molecules more bioavailable?

Answer 6

-modulates binding to human serum albumin
-reduces metabolism (C-F is stronger bond than C-H so is harder for cytochrome P450 to oxidise)

Question 7

How does fluorination make drug molecules more lipophilic?

Answer 7

-F is v. electronegative so makes surrounding groups (eg. amino or carboylate groups) less basic (higher pKa)
-being more lipophilic makes compounds with amino groups better distributed

Question 8

What is the exception for fluorination making drug molecules more lipophilic?

Answer 8

when F adjacent to O
-because O more polarised so can form stronger H-bonds with water
-or because overall polarity charge is higher so has a higher solvation energy in aq soln

Question 9

What effect does having chiral centres have on a drug?

Answer 9

-allows drug to bind to chiral compounds (eg. proteins)
-specific to one enantiomer

Question 10

How are xenobiotic (foregin) compounds (eg. drugs) metabolised by the body?

Answer 10

-oxidised by cytochrome P450 isozymes (complicated cycling involving adding O from O2, producing water, using NADPH)
-conjugation -funct group added to make drug recognisable for removal

Question 11

What happens in excretion?

Answer 11

-kidney filters blood and some compounds excreted as urine, others reabsorbed
-compounds not filtered go to liver, where they get converted to bile to go to intestine, further metabolised or reabsorbed (re-entering circulation)