Exam 1 Flashcards
Identify the pharmacophore from the structure of drugs with similar
biological activities.
Drugs that bind to the same target share a similar structural motif (pharmacophore).
The structural motif is mostly responsible for the binding to the receptor.
Other parts of the drugs still affect various important drug properties (agonism-antagonism, solubility, membrane crossing, metabolism, etc.).
Define the structure-activity relationship.
The properties of a drug depend on the chemical constituents of the molecule.
How tightly a drug interacts with the target
How soluble a drug is in water
How well a drug cross the biological membranes
How fast a drug is degraded in the body
By modifying the structure, one can change the drug properties.
By examining the structure, one can predict the drug properties.
List the chemical properties of drugs that can be deduced from the
structure.
- Size
- Ionization
- Solubility
- Hydrophobicity
- Stereochemistry
List the key chemical properties of drugs that affect their biological
activities.
- Membrane permeability
- Target binding
- Metabolism
- Excretion
Identify the drug properties that are affected by the change in pH.
pH affects the ionization of a drug molecule.
Identify ionizable groups in drug structures.
Look for protons
Predict the ionized form of drugs from their structures.
Look for protons
Estimate the degree of drug ionization at a given pH using Henderson-Hasselbalch equation.
pH= pKa +log ([ A − ]/[HA ])
When pH < pKa, [A–] < [HA]
When pH > pKa, [A–] > [HA]
Predict the range of pH where a drug would be more soluble in water.
Water is a polar solvent; polar molecules dissolve better in water (“like dissolves like”).
H-bond donors and acceptors
Ionic groups
Better solubility can be achieved by changing pH.
List the different modes of drug permeation into the body.
GI tract and blood brain barrier as well as lipid membranes of the target cells act as physical barriers.
Most drugs are absorbed through membranes by passive diffusion.
The absorption rate of a drug is related to the drug’s lipophilicity (in general, more lipophilic drugs are absorbed more efficiently).
Order a series of drugs according to their efficiency in passive
diffusion.
Identify hydrophobic and hydrophilic groups in a drug structure.
Hydrophilic: Typically polar and capable of H-bond formation
Hydrophobic: Typically non-polar hydrocarbons
Identify hydrogen bonding donors and acceptors in a drug
structure.
Predict the effect of a structural change in a drug on its solubility in
water.
Explain how logP values affect the ability of drugs to reach target
sites.
Bigger LogP → more lipophilic (more hydrophobic)
LogP < 0 The drug favors water.
LogP = 0 Equal distribution
LogP > 0 The drug favors 1-octanol
Explain why the relationship of drug effectiveness versus logP is
parabolic.
The optimal logP (logP0) is the logP value corresponding to the maximum of the drug activity.
Lipophilicity improves drug permeation, but too much lipophilicity may hinder membrane crossing.
Calculate ClogP of a drug molecule from the π values of its constituent groups.
The calculated logP (ClogP) is a sum of π values of the fragments.
Calculate the π value of a constituent group from logP values of structurally related drugs.
Estimate logD using logP and pKa at a given pH.
Drug HA is an acidic drug with logP = 2 and pKa = 4.
At pH = 1, [A–]aq is negligible compared with [HA]aq→ D ~ P
At pH = 7, [A–]aq is much greater than [HA]aq → D ≪ P
At higher pH, logD (the effective logP) is much less than the actual logP → the drug may NOT cross the lipid membrane well.
Predict the efficiency of passive diffusion of a drug with a known pKa at a given pH.
Ionized drugs cannot cross the lipid bilayer.
Passive diffusion of a drug is more efficient at a pH where the drug is mostly neutral.
Even if a drug is mostly ionized at a given pH, the drug still diffuse through the lipid bilayer.
The un-ionized neutral drug is still in equilibrium with the ionized drug.
Predict where a drug will be absorbed in the digestive system based on the drug’s pKa value.
Drugs are absorbed best at pH, where they are mostly neutral.
Most drugs are absorbed in the jejunum, where the pH is generally between 5 and 7.
Acidic drugs tend to be absorbed in the stomach, where the pH is generally between 1 and 3.
Explain how the electronic effects of substituent groups affect drug ionization, acidity, and basicity.
