PSW710 Introduction to Pharmaceutical Sciences

Homework Assignment for the Section on

Physicochemical Properties of Drugs and QSAR

Name:
Questions:
1) Explain why chiral recognition is important in the binding of small molecule ligands to targets. (4 pts.)

2) Explain the term Bioisostere and what is the intent of or what is to be gained from using bioisosteric
equivalents? (5 pts.)
A bio- isostere is a group that can be used to replace another group while retaining the desired
biological activity.Bioisosterism is the application of isosterism to biological systems and guides
molecular modification of drugs to produce desired changes in either the drug’s physicochemical
properties or bio- logical actions. bioisosteres are commonly used in drug design to replace a
problematic group while retain- ing activity. In some situations, the use of a bioisostere can actually
increase target interactions and/or selectiv- ity. For example, a pyrrole ring has frequently been used
as a bioisostere for an amide. Carrying out this replace- ment on the dopamine antagonist sultopride
led to increased activity and selectivity towards the dopamine D3-receptor over the dopamine D2-
receptor
3) Why is ionization important for protein–ligand interactions? (4 pts.)

The proteins that are typically chosen for drug targets perform their cellular func- tions by
interacting with chemical mes- senger molecules called ligands.In most cases, the initial attraction
between the protein and the ligand is provided by a long-range force such as an ionic inter- action
between opposite charges on the protein binding site and the ligand.Because the initial interaction
between a ligand and protein is often ionic, the ionization state of weak acid and base drugs is
very important. Charged atoms (from ionized amino acids) often line the protein active site,
imparting a localized charge in specific regions of the pocket. Opposite charges on the active site
and ligand will attract each other, beginning the process of forming the complex
4) Circle the acidic protons on the compound below and identify the one with the greatest degree of
ionization at pH = 7.4 by marking it with an asterix (*). (4 pts.)

5) The structures below are classified as benzodiazepines, drugs used to treat anxiety and insomnia.
Structure I represents the pharmacophore for this chemical class. Changing the lipophilicity of the
molecule can alter the ability of the drug to enter the brain and therefore, how fast the drug can
produce its effects.

For structures II and III, compare each to structure I and determine if the analogs are more or less
lipophilic than structure I. (4 pts.)

6) Briefly explain the concept of SAR (Structure Activity Relationships). List the four (4) key factors
effecting SAR. (6 pts.)
7) Briefly explain the difference between SAR and QSAR: (5 pts.)

8) Glyburide (Micronase®) is a weak acid drug used in the treatment of diabetes. It has a pKa = 6.8.

What percentage of glyburide is ionized in the small intestines at pH = 5.8? (2 pts.)

Draw the structure of the conjugate base along with the correct charge? (2 pts.)
 9) Naproxen (Aleve®) is an anti-inflammatory drug with a molecular weight of 230 and a pKa = 4.2. It has
the following structure:

At what pH will the concentration of the conjugate acid and conjugate base be equal? (2 pts.)

What fraction of naproxen is ionized in a buffer at pH 3.2? (2 pts.)

What fraction of naproxen is ionized in a buffer at pH 6.2? (2 pts.)

10) What is meant by the term LogP? (4 pts.)

Partition coefficient is often stated as a logarithmic value (log P).The balance between
lipophilicity and hydrophilicity of a compound in its un-ionized, nonelectrolyte form is charac-
terized by a parameter called its partition coefficient P. In other words, P is a mea- sure of
relative affinity of the compound for lipids as compared to water. In the laboratory, P is
determined by measuring the relative solubility of a compound in water and in a lipid
What is the approximate range of desirable LogP values for a drug assuming you are following Lipinski’s
Rule of Fives?
0<logp<3.5 (2 pts.)

What is the primary problem if the LogP value is outside of this range? (2 pts.)

Log P .> 3.5 (or logP . 3000) are usually too lipophilic to be good drugs because they tend to be
poorly soluble in aqueous biological fluids, or tend to concentrate in lipid environments.