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Patrick: An Introduction to Medicinal Chemistry 3/e

Chapter 3: Proteins as drug targets


Answers
1)
Ph

O
H2N
Me

H
N

N
H

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=

Aminoacid
structure

O HBA
H
HBD

vdw

Noside
chain

Asparticacid

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

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Patrick: An Introduction to Medicinal Chemistry 3/e


Chapter 3: Proteins as drug targets
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

TM1 TM2

TM3

CO2H

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

+manyotherpeptides

For example, there is nothing to stop alanine coupling with itself, or valine
coupling with itself to form L-alanyl-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.

OXFORD H i g h e r E d u c a t i o n
Oxford University Press, 2006. All rights reserved.

Patrick: An Introduction to Medicinal Chemistry 3/e


Chapter 3: Proteins as drug targets

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

H
R

Serine

CO2H

Tyrosine

Threonine

R=
HBA O

HBD H
alcohol
Phosphorylation

H HBD

alcohol
Phosphorylation

P
O

phenol

Phosphorylation

O
O

HBD
H
O
HBA

CH3 HBA

O
CH3

O
O

O
O

O
P

The 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.

OXFORD H i g h e r E d u c a t i o n
Oxford University Press, 2006. All rights reserved.