EXAM 1 - Physiochemical Properties of Drug Molecules

Question 1

Describe the scaffold model.

Answer 1

Scaffold is a central framework of drug molecules
- you can design similar drugs with the same scaffold and different

Question 2

3D structure is controlled by what?

Answer 2

• static arrangement of gorups around a stereogenic center
• conformation of a molecule (very dynamic)

Question 3

Which of the following hybridization states is consistent with a trigonal planar structure for N atoms?

Answer 3

sp2

Question 4

Which is more favorable? cis? or trans?

Answer 4

trans is more energetically favorable

Question 5

Explain Chan-Ingold-Prelog priority

Answer 5

the group that has the highest atomic number gets the higher priority

Question 6

True or false: a molecule can only be considered cis or trans when it contains two hydrogens

Answer 6

true

Question 7

Z versus E configuration

Answer 7

Z - priority groups are on the same side
E - priority groups are on opposite sides

Question 8

Define enantiomer

Answer 8

non-superimposable mirror image
r - clockwise
s - counterclockwise

Question 9

What makes enantiomers different from eachother?

Answer 9

They have the same chemical and physical properties, but they have different biological properties in the body (binding affinity)

Question 10

define diastereomers

Answer 10

completely different compounds
different physical, chemical, and biological properties

Question 11

Why do enantiomers have different binding affinities?

Answer 11

Since proteins are chiral, interactions with drugs will give two serperate energies

Question 12

The more active enantiomer is called the ….

Answer 12

Eutomer

Question 13

the less active enantiomer is called the ….

Answer 13

distomer

Question 14

What is the eudistomer ratio?

Answer 14

the activity ratio of the eutomer and distomer

Question 15

What are conformational isomers?

Answer 15

Isomers of a single compound that are related by changes in rotation around ONE single bond.
- bioactive conformation perfectly fits into the receptor

Question 16

What happens when there’s a ring flip on a cyclic molecule?

Answer 16

equatorial up –> axial up
axial down –> equatorial down

Question 17

Define Bronstead acid and base

Answer 17

acid - donates a proton
base - accepts a proton

Question 18

What is the henderson-hasselbach equation?

Answer 18

pKa = pH - log(A-/HA)

Question 19

What happens when [A-] = [HA]?

Answer 19

When [A-] and [HA] are equal, pH = pKa.
This means that at that pH, half of the molecule is ionized and half is unionized.

Question 20

You can think of pKa as affinity for protons. When pKa < pH…

Answer 20

When pKa < pH, deprotonation occurs
lower pKa = lower affinity

Question 21

How does ionization have an effect on drug absorption and solubility?

Answer 21

• an ionized drug is going to be more water soluble and more hydrophillic; it is going to have a hard time absorbing through the cell membrane
• an unionized drug is going to be more lipid soluble and more hydrophobic; it is going to absorb easier into the cell membrane.

Question 22

What are the four main drug targets?

Answer 22

lipids, proteins, carbohydrates, and nucleic acids

Question 23

Characteristics of drug targets

Answer 23

• macromolecules
• much smaller than drug targets bc they fit into the hollow, hydrophobic binding sites on macromolecules
• typically involve intermolecular bonds (dynamic between bound and unbound)
• most drug are in equillibrium between bound and unbound

Question 24

What happens when a drug binds to its target?

Answer 24

results in induced fit and there will be a conformational change

Question 25

pKa = pH when…

Answer 25

[A-] = [HA]

Question 26

How do drugs move around the body?

Answer 26

bulk flow transfer - cardiovascular system provides rapid distribution of molecules throughout the body

Question 27

how do drugs move into the cells?

Answer 27

diffusional transfer - transfer of molecules across the cell membrane (dependent on the drug structure)

Question 28

What is logP value?

Answer 28

the balance between hydrophilicity and lipophilicity with a window to allow for both characteristics
ex. -3 < X 5

Question 29

what is the partition coefficient?

Answer 29

determines how hydrophobic a drug is
P = [drug in octanol]/[drug in water]
(high [drug in octanol] = high hydrophobicity)

Question 30

what is pi? how do you measure it? what does it tell you?

Answer 30

pi is the lipophilic substituent constant
pi = logPx - logPh
where Ph is the P of the standard compound and Px is P of the monosubstituted derivative
pi tells you how hydrophobic the substituent is relative to the standard compound with just hydrogen

Question 31

what does a positive pi value mean? negative value?

Answer 31

positive pi value means that the substituent is more hydrophobic then the standard compound.

negative pi value means the substituent is less hydrophobic than the standard compound.

Question 32

Rule of thumb for solubility:

Answer 32

LogP > 0.5 —> low solubility in water
LogP < 0.5 —> high solubility in water

Question 33

Lipinski’s rule of five

Answer 33

if the drug meets 2 or more criteria, it is not a good oral drug
1) more than 5 hydrogen bond donors
2) more than 10 hydrogen bond acceptors
3) MW is greater than 500 g/mol
4) logP is greater than 5

Question 34

how do you calculate logP using pi values?

Answer 34

LogP (theory) = logP (benzene) + piCl + piCONH2

Question 35

what is logD used for?

Answer 35

logD measures where the drug is ionized and unionized
the higher logD is, the more hydrophobic the drug is