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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

O

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

H

Glycine

Phenylalanine

CO2H

R

R=

Amino acid
structure

H

O HBA
H
HBD

vdw

No side
chain

Aspartic acid

Lysine
HBA
O

R=
HBA
H
HBD

N

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

R

R

N
H

R

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.

This is likely to result in racemisation of asymmetric centres. 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. tetrapeptides etc. or valine coupling with itself to form Lalanyl-L-alanine and L-valyl-L-valine respectively. H2N H CO2H CH3 + H2N H3C H CO2H CH3 H2N H O N CH3 H H CO2H + many other peptides For example.However. There is also no reason why any of the above dipetides that are formed could not undergo a further coupling reaction to form tripeptides. there is nothing to stop alanine coupling with itself. dicyclohexylcarbodiimide) in order to achieve milder. 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. .g. the phosphate groups are ionised and will interact with ionic groups rather than hydrogen bonding groups. When the groups are phosphorylated. It is also important to have coupling reagents (e. H H2N O N CH3 H H 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. Due to these problems. non-racemising conditions. Both f these functional groups can form hydrogen bonds. The reaction is also likely to need forcing conditions since one is attempting to form an amide between an amine and a carboxylic acid. 6) The functional groups involved are alcohols and phenols. 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.

6).H2N H R Tyrosine Threonine Serine CO2H R= HBA O H HBD H alcohol Phosphorylation O H HBD HBD H O HBA CH3 HBA alcohol phenol Phosphorylation Phosphorylation O O O P O H O O CH3 P O O O O O P O he tertiary structure will alter as a result (see section 6.5. The one letter coding is ELPDVVAFKSGGT T . 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.