Page 109 - Medicinal Chemistry Self Assessment

3. Shown below is the structure of imipramine as well as three analogs. Evaluate each analog and provide an
overall evaluation of how each change will affect the chemical properties of imipramine.
N
CH
3
N
CH
3
3
N CH Cl Imipramine N N N CH 3 CH 3 N N O CH 3
Analog A CH 3 Analog B CH 3 Analog C CH 3

98 Medicinal Chemistry Self Assessment
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side chains of the
four amino acids have been boxed.
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side
chains of the four amino acids have been boxed.

a. Identify the four amino acids that comprise this tetrapeptide sequence.
Answer

Tyrosine (Tyr)—Aspartic Acid (Asp)—Valine (Val)—Glutamine (Gln)

b. For each amino acid, identify the key chemical properties of its highlighted side chain.
Answer
Tyrosine: This side chain is one of the largest seen in amino acids and is involved in dictating
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the overall conformation of the peptide. Although the phenyl ring is hydrophobic, the phenolic
hydroxyl group can act as both a hydrogen bond donor and acceptor and contributes to the
overall water solubility.

Aspartic Acid: This side chain is acidic and will most likely be ionized at physiological pH. This will
enhance the overall water solubility of the peptide. It will most likely reside in a water soluble
pocket of the overall peptide.
Valine: This is an aliphatic, lipid soluble, hydrocarbon side chain. It contributes to the overall lipid
solubility of the peptide and can contribute to lipid soluble pockets within the peptide. Addition-
ally, the isopropyl side chain can impart some steric bulk that may influence the overall conforma-
tion of the molecule.
Glutamine: Overall, this side chain is normally classified as a polar, water soluble side chain due to
its ability to act as both a hydrogen bond donor and acceptor. The two methylene carbon atoms
allow the amide to be oriented in different locations and may contribute a little to the overall
lipid solubility of the peptide.

Go to Section 1.3 [Link to section 1.3 title]
Note: References to chapters are to Chapter 3 in Harrold MW and Zavod RM, Basic Concepts in Medicinal
Chemistry, American Society of Health-System Pharmacists, ©2013.