EXAM 1 - Physiochemical Properties of Drug Molecules Flashcards
Describe the scaffold model.
Scaffold is a central framework of drug molecules
- you can design similar drugs with the same scaffold and different
3D structure is controlled by what?
- static arrangement of gorups around a stereogenic center
- conformation of a molecule (very dynamic)
Which of the following hybridization states is consistent with a trigonal planar structure for N atoms?
sp2
Which is more favorable? cis? or trans?
trans is more energetically favorable
Explain Chan-Ingold-Prelog priority
the group that has the highest atomic number gets the higher priority
True or false: a molecule can only be considered cis or trans when it contains two hydrogens
true
Z versus E configuration
Z - priority groups are on the same side
E - priority groups are on opposite sides
Define enantiomer
non-superimposable mirror image
r - clockwise
s - counterclockwise
What makes enantiomers different from eachother?
They have the same chemical and physical properties, but they have different biological properties in the body (binding affinity)
define diastereomers
completely different compounds
different physical, chemical, and biological properties
Why do enantiomers have different binding affinities?
Since proteins are chiral, interactions with drugs will give two serperate energies
The more active enantiomer is called the ….
Eutomer
the less active enantiomer is called the ….
distomer
What is the eudistomer ratio?
the activity ratio of the eutomer and distomer
What are conformational isomers?
Isomers of a single compound that are related by changes in rotation around ONE single bond.
- bioactive conformation perfectly fits into the receptor
What happens when there’s a ring flip on a cyclic molecule?
equatorial up –> axial up
axial down –> equatorial down
Define Bronstead acid and base
acid - donates a proton
base - accepts a proton
What is the henderson-hasselbach equation?
pKa = pH - log(A-/HA)
What happens when [A-] = [HA]?
When [A-] and [HA] are equal, pH = pKa.
This means that at that pH, half of the molecule is ionized and half is unionized.
You can think of pKa as affinity for protons. When pKa < pH…
When pKa < pH, deprotonation occurs
lower pKa = lower affinity
How does ionization have an effect on drug absorption and solubility?
- 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.
What are the four main drug targets?
lipids, proteins, carbohydrates, and nucleic acids
Characteristics of drug targets
- 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
What happens when a drug binds to its target?
results in induced fit and there will be a conformational change
pKa = pH when…
[A-] = [HA]
How do drugs move around the body?
bulk flow transfer - cardiovascular system provides rapid distribution of molecules throughout the body
how do drugs move into the cells?
diffusional transfer - transfer of molecules across the cell membrane (dependent on the drug structure)
What is logP value?
the balance between hydrophilicity and lipophilicity with a window to allow for both characteristics
ex. -3 < X 5
what is the partition coefficient?
determines how hydrophobic a drug is
P = [drug in octanol]/[drug in water]
(high [drug in octanol] = high hydrophobicity)
what is pi? how do you measure it? what does it tell you?
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
what does a positive pi value mean? negative value?
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.
Rule of thumb for solubility:
LogP > 0.5 —> low solubility in water
LogP < 0.5 —> high solubility in water
Lipinski’s rule of five
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
how do you calculate logP using pi values?
LogP (theory) = logP (benzene) + piCl + piCONH2
what is logD used for?
logD measures where the drug is ionized and unionized
the higher logD is, the more hydrophobic the drug is
