CHEM3071.

03 (W) Pharmaceutical Discovery

Professor Michael G. Organ
Campus Address: Room 460, Chemistry Building (CB)
Phone: (416) 736-5313
E-mail: organ@yorku.ca
Web address: http://www.yorku.ca/organ/teaching

Answers to Questions in Chapter 3 in An Introduction to Medicinal Chemistry

by Graham L. Patrick
1)

Ph

O
H2N
Me

N
H

O
H
N

OH

2) Glycine is the only amino acid with no side chain and is the only naturally occurring amino acid that is not
asymmetric.
3) Possible interactions are shown below for the side chains of serine, phenylalanine, glycine, lysine and
aspartic acid (HBA= hydrogen bond acceptor; HBD = hydrogen bond donor; vdw = van der Waals interactions)
Serine
H2N

Glycine

Phenylalanine

CO2H

R=

Amino acid
structure

O HBA
H
HBD

vdw

No side
chain

Aspartic acid

Lysine
HBA
O

R=
HBA
H
HBD

O
HBA
H
HBD

ionic

H
HBD

N
HBDH H H
HBD
HBD

HBA
O
O
HBA/ionic

3) The peptide bond is planar since it is possible for the nitrogen lone pair to interact with the carbonyl group
as follows.
O
R

O
N
H

N
H

4) If a sequence of amino acids with hydrophobic side chains can be identified in the primary structure, it is
possible that this is a transmembrane (TM) region of the protein (i.e it is located within the cell membrane as
shown below) This is because hydrophobic side chains would interact more favourably with the fatty cell
membane than with the aqueous environments on either side of the cell membane. Regions of the protein that
are made up predominantly of polar side chains are almost certainly located intracellularly or extracellularly.

However, it would be wrong to conclude that all amino acids with hydrophobic side chains are located in
transmembrane regions and all amino acids with polar side chains are located intracellularly or extracellularly.

H2N

Extracellular
loop
CO2H

TM1 TM2

TM3

Cell
membrane

TM4

Intracellular
loop

Intracellular
loop

5) The structure of L-alanyl-L-valine is shown below.

H2N

O
N

CH3

CO2H

An attempt to couple alanine directly to valine may well produce the desired products but a whole range of
other structures will also be formed.

H2N

CO2H

CH3

H2N
H3C

CO2H
CH3

H2N

O
N

CH3

CO2H

+ many other peptides

For example, there is nothing to stop alanine coupling with itself, or valine coupling with itself to form Lalanyl-L-alanine and L-valyl-L-valine respectively.
There is also no reason why any of the above dipetides that are formed could not undergo a further coupling
reaction to form tripeptides, tetrapeptides etc.
The reaction is also likely to need forcing conditions since one is attempting to form an amide between an
amine and a carboxylic acid. This is likely to result in racemisation of asymmetric centres.
Due to these problems, it is necessary to protect the amino group of one amino acid and the carboxylic acid of
the other before a coupling reaction is attempted. It is also important to have coupling reagents (e.g.
dicyclohexylcarbodiimide) in order to achieve milder, non-racemising conditions.
6) The functional groups involved are alcohols and phenols. Both f these functional groups can form hydrogen
bonds. When the groups are phosphorylated, the phosphate groups are ionised and will interact with ionic
groups rather than hydrogen bonding groups.

H2N

Tyrosine

Threonine

Serine

CO2H
R=

HBA O

HBD H
alcohol
Phosphorylation

H HBD
HBD
H
O
HBA

CH3 HBA

alcohol

phenol

Phosphorylation

Phosphorylation

O
O
O

P
O

H
O

O
CH3

O
O

O
O

O
P

he tertiary structure will alter as a result (see section 6.5.6).

7) Glu-Leu-Pro-Asp-Val-Val-Ala-Phe-Lys-Ser-Gly-Gly-Thr
The question already shows the three letter coding for this polypeptide. The one letter coding is
ELPDVVAFKSGGT