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Chapter 1

1) The ability of a molecule to cross the fatty cell membrane has little to do with its size, but
more with its hydrophobic character.
Estrone is more hydrophobic than adrenaline since it has a larger carbon skeleton and only
two polar functional groups. Thus, the molecule is hydrophobic in character and can dissolve
through the fatty cell membrane.
Adrenaline has four polar functional groups and a much smaller carbon skeleton. Thus, the
polar functional groups dominate in determining the character of the molecule making it very
polar and unlikely to pass through the cell membrane.

Ketone
Alcohol CH O 3
OH
Phenol
HO NHMe
Amine
Phenol
HO Phenol
HO
Adrenaline Estrone

There is another factor which hinders adrenaline's ability to cross the cell membrane. In
aqueous solution, the four polar groups will be highly solvated with water molecules. In order
to cross the cell membrane, these water molecules have to be 'stripped away' and this
involves an energy penalty. The energy of desolvation for estrone is less since it has only two
polar functional groups solvated.

2) Valinomycin has a macrocylic structure where carbonyl oxygens are pointed towards the
centre, making this area polar and capable of accommodating a polar ion. The outside of the
ring is dominated by alkyl side chains which are hydrophobic in nature. As a result, the
molecule can dissolve easily in fatty cell membranes and encapsulate polar ions, allowing
these ions to be transported across cell membranes. Further details are provided in section
10.6.2.

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L-Lactate
L-Valine Me D-Valine
H Me Me
Me NH H Me Hydrophobic
D-Hyi
O side chains
Me H O H
Me D-Hyi
O NH
O
Me O Me
HN O O H
H Polar O
Me Me
O centre
O L-Valine
D-Valine
Me O
O O H Me D-Hyi =
H O O NH D-Hydroxyisovaleric acid
O
Me Me
L-Lactate HN
O H L-Lactate
H
O NH Me
Me H H
Me Me MeD-Valine
L-Valine Me
D-Hyi

Valinomycin

3) The alkyl chains are linked to the glycerol skeleton by ether linkages rather than by ester
linkages. Ethers are chemically more stable than esters to extreme conditions.
ether link

Branching Branching Branching Branching O

O P OCH2 CH2NH3
O
O H

O
glycerol
skeleton
ether link

The long alkyl chains are also branched, unlike those in eukaryotic cell membranes.
Branching makes the chains more resistant to oxidation.

4) The alkyl group is hydrophobic and is embedded into the cell membrane. As a result, the
drug is anchored to the cell membrane and is located on its outer surface such that it is
ideally located to interfere with cell wall synthesis. Further details can be found in section
[Link].

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HO CH2OH
Alkyl anchor
O
HO O

OH N O
H Cl
HO NHAc O O
C D E
HO O Cl OH
O
O O
H H H H O
O N O NH3
N N N H
H H
O H N H
N CO2
H
H
B
HO OH
A
O
HO OH
O
HO
O
OH
HO
OH

Teicoplanin

Alky l chain anchor

Cell membrane

5) A hydrophobic chain could be attached to the Ras protein which would serve to anchor it to
the inner surface of the cell membrane. This is similar to the way teicoplanin is anchored to
the outer surface of cell membranes (compare answer 4 above). The hydrophobic chain is
attached to the Ras protein via a cysteine residue as shown below. More details can be found
in section 21.6.1.

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Val Met
O O S O O S
H H H H
N N OH N N OH
Ras N N Ras N N
H H H H
Cys O O O O
HS S
FTase

PPO
farnesyl diphosphate
Further processing
O
H
N
Ras OMe
Methyl ester
S

6) Cholesterol has one polar group - the alcohol group. This can form a H-bond to the polar
head group of phospholipids. The rest of the molecule is hydrophobic and will sink into the
cell membrane to form hydrophobic interactions with the alkyl side chains of the
phospholipids.

Polar OH
Head
Group

CH 3

Hydrophobic Tails

CH 3
CH3
H
H

H3C

CH3

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7) cis-Double bonds introduce a kink into the chain which will hinder the regular packing of
the hydrophobic chains. This increases the fluidity of the cell membrane.

NM e3 NMe3

(CH2) 2 (CH2 )2

O O

O P O O P O

O O

CH2 CH CH2 CH2 CH CH2

O O O O
O O O O

cis trans

8) The relative order of H-bonding strength is shown below

O O O O
C C C C
O R RHN R R R RO R

Increasing strength of carbonyl oxygen as a hydrogen bond acceptor

This reflects the fact that the greater the electron density on the carbonyl oxygen, the
stronger it will act as a hydrogen bond acceptor. The carboxylate group is the strongest
hydrogen bond acceptor since a full negative charge is shared between both oxygens.
The carbonyl oxygen of the amide will also act as a good hydrogen bond acceptor because
the lone pair of electrons on nitrogen interacts with the carbonyl group as shown below. This
increases electron density on the carbonyl oxygen.

O O
R C R C
N R N R
H H
Amide - N acts as poor HBA
O acts as a good HBA

No such interaction occurs for the ketone or ester carbonyl groups, but the carbonyl groups
are still polarised resulting in the oxygen having a slightly negative charge. Consequently the

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carbonyl oxygen in these functional groups can still act as a hydrogen bond acceptor, but less
strongly.

9) The diagram below shows the possible intermolecular bonding interactions for the various
functional groups present in each molecule (HBA = hydrogen bond acceptor; HBD =
hydrogen bond donor; vdw = van der Waals interactions)

HBD HBA H3C H

H HBA HBD CH3 O CH3
O H dipole-dipole
HBA H CH
HBD O N HBA CH3
H Me
vdw HBD
H vdw HBD
H vdw
HBD O H
HBA O O
HBA HBA
Adrenaline Estrone Cholesterol

Notes
* It cannot be assumed that all the interactions shown actually occur.
* Adrenaline can also exist in the ionised form, resulting in the potential interactions shown
below.

HBD
H HBA HBD
HBA O H
H HBD
HBD O N
H Me
vdw ionic
H
HBD O
HBA
Adrenaline

* The remainder of the carbon skeleton in each molecule has the potential to interact with
other hydrophobic molecules through van der Waals interactions. This is particularly the case
for the steroid structures.
* The oxygen atoms of phenols and aromatic ethers are considered to be weak hydrogen
bond acceptors.
* The aromatic rings of adrenaline and estrone also have the potential to form
interactions with aromatic or heteroaromatic rings in target binding sites.

10) Trade names are in brackets.

Amoxicillin (Amoxil)

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H2N H H H H
N S
Me
O
HO N Me
Phenol O
CO2H

Ranitidine (Zantac)

4 3
Me2N CHNO2
5
2 S
O N NHMe
H

Gefitinib (Iressa)

HN Cl O
O N
N

N OMe

Atracurium (Tacrium)

MeO OMe
Me H
N O O N
MeO OMe
O O

OMe MeO
OMe OMe

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Chapter 2

1)

Ph
O O
H
H 2N N
N OH
H
Me 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, aspartic acid and aspartate (HBA= hydrogen bond acceptor; HBD = hydrogen
bond donor; vdw = van der Waals interactions). An aromatic ring can also form
interactions with another aromatic or heteroaromatic ring.

Serine Phenylalanine Glycine

H
H2N CO2H
R= H
R O HBA
vdw No side
Amino acid H
structure HBD chain

Lysine Aspartic acid Aspartate

HBA HBA
O O
R=
O ionic
O
H HBA
HBA ionic HBA
HBD
N N
H H H H
HBD H HBD
HBD HBD
HBD

4) In the primary structure of the protein, a sequence of amino acids with hydrophobic side
chains may indicate a transmembrane (TM) region (i.e it is located within the cell membrane
as shown below). This is because hydrophobic side chains will 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.

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

H2N Extracellular
loop
CO2H

Cell
TM1 TM2 TM3 TM4 membrane

Intracellular
loop Intracellular
loop

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

O
H
H2N
N CO2H
H
CH3 H

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

H H O
H2N CO2H H2N CO2H H
+ H2N + many other peptides
N CO2H
CH3 H
H3C CH3 CH3 H

For example, L-valyl-L-alanine is an equally likely product. There is also nothing to stop
alanine coupling with itself, or valine coupling with itself to form L-alanyl-L-alanine and L-valyl-
L-valine respectively.
Furthermore, there is no reason why any of the above dipetides that are formed could not
undergo further coupling reactions 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 which are more likely to form a salt at room
temperature. Forcing conditions are 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

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have coupling reagents (e.g. dicyclohexylcarbodiimide) in order to achieve milder, non-

racemising conditions.

6) The functional groups involved are alcohols and phenols. Both of 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.

H Serine Threonine Tyrosine

H2N CO2H
R=
R
H HBD
HBA O H O HBD
CH3 HBA
HBD H H
O
HBA
alcohol alcohol phenol

Phosphorylation Phosphorylation Phosphorylation

O
O Ionic
P
O H O O O
CH3 O
P Ionic P
O O O O
O
Ionic

The tertiary structure will alter as a result (see section 5.2.6).

7) Glu-Leu-Pro-Asp-Val-Val-Ala-Phe-Lys-Ser-Gly-Gly-Thr

The one letter coding is ELPDVVAFKSGGT.

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Chapter 3

1) The enzyme-catalysed reduction of an aldehyde requires one equivalent of the cofactor

NADH, which is oxidised to NAD+. However, if ethanol is added to the reaction, aldehyde
dehydrogenase can catalyse its oxidation to acetaldehyde. In the process, NAD+ is converted
back to NADH. As a result, only a catalytic quantity of NADH is required.
It is important to appreciate that enzymes can catalyse reactions in either direction until an
equilibrium is reached. In this case two separate reactions involving the same enzyme are
coupled together to recycle the cofactor.

Aldehyde dehydrogenase
Aldehyde Alcohol

NADH NAD+

Aldehyde dehydrogenase
Acetaldehyde Ethanol

2) Acetylcholine contains an ester functional group and a quaternary nitrogen which is

charged. Thus, hydrogen bonds and ionic interactions may be important. There are also
methyl groups present which might fit into hydrophobic pockets and interact via van der
Waals interactions. The actual binding interactions for acetylcholine are discussed in section
22.5 and include the possibility of induced dipole interactions between the quaternary
ammonium group of acetylcholine and aromatic/heteroaromatic groups of amino acid side
chains.

HBA
O H 3C
CH3
C N
H3C O CH3
HBA
ionic

3) A mechanism similar to that described for the hydrolysis of peptide bonds by chymotrypsin
(section 3.5.3) would be feasible, involving a catalytic triad of serine, histidine and aspartate
(or glutamate). Serine would serve as a nucleophile, histidine as an acid/base catalyst and
aspartate (or glutamate) as an activating and orientating group. The actual mechanism for the
hydrolysis of acetylcholine is described in section [Link].

4) In general, binding interactions will involve acetylcholine being bound in a particular

conformation such that the binding interactions are maximised. As a result, certain bonds
might be placed under strain with the result that they are broken more easily. For example, a
hydrogen bond involving the carbonyl oxygen of acetylcholine may result in the weakening of
the carbonyl bond such that it is more easily broken in the first stage of the enzyme-

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catalysed mechanism. Note also that the strength of this interaction is likely to be more
significant for the transition state compared to the substrate itself. In this way, the transition
state will be stabilised more significantly than the substrate, resulting in a lowering of the
activation energy.

5) The following table shows the values necessary for both the Michaelis Menten and
Lineweaver-Burk plots.

Substrate concentration [S] (mol dm-3)

Initial rate (J) (mol dm-3 s-1)
1/(substrate concentration) (1/[S]) (mol-1 dm3)
1/Initial rate (1/J) (mol-1 dm3 s)

[S] J 1/[S] 1/J

0.05 28.6 20 0.035

0.10 51.5 10 0.0194
0.25 101 4 0.0099
0.50 141 2 0.0071
1 172 1 0.0058

The Lineweaver-Burk plot has 1/Initial rate (1/J) on the y-axis and 1/[S] on the x-axis. This
should give a straight line having an intercept of 0.00400 on the y-axis and a slope of
0.00155. Therefore, the maximum rate of reaction = 1/intercept = 250.2 mol dm-3 s-1
KM = slope x (maximum rate of reaction) = 0.387 mol dm -3 The maximum rate of
reaction is achieved at high substrate concentration. KM is the Michaelis constant and
corresponds to the substrate concentration at which the initial rate of reaction is half of Jmax.
Therefore, the maximum rate of reaction = 1/intercept = 250.2 mol dm-3 s-1 KM =
slope x (maximum rate of reaction) = 0.387 mol dm -3 The maximum rate of reaction is
achieved at high substrate concentration. KM is the Michaelis constant and corresponds
to the substrate concentration at which the initial rate of reaction is half of Jmax.
KM = slope x (maximum rate of reaction) = 0.387 mol dm -3 The maximum rate of reaction
is achieved at high substrate concentration. KM is the Michaelis constant and corresponds
to the substrate concentration at which the initial rate of reaction is half of Jmax.
The maximum rate of reaction is achieved at high substrate concentration. KM is the
Michaelis constant and corresponds to the substrate concentration at which the initial rate of
reaction is half of Jmax.
KM is the Michaelis constant and corresponds to the substrate concentration at which the
initial rate of reaction is half of Jmax.

A Michaelis Menten plot of the maximum rate of reaction versus substrate concentration
shows a curve where the line is approaching a maximum plateau, but has not yet reached it.
Therefore, any attempt to define the maximum rate of reaction from this kind of plot can only
be an estimate. Since we need to know the maximum rate of reaction in order to define KM,

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the value of KM will also be inaccurate. The Lineweaver-Burk plot gives a straight line and
allows us to define the maximum rate of reaction and KM more accurately.
The Lineweaver-Burk plot gives a straight line and allows us to define the maximum rate of
reaction and KM more accurately.

6) In the unmutated version of lactate dehydrogenase, there is a glutamine residue in the

active site which contains a neutral primary amide group at the end of the side chain. In the
mutated version of the enzyme, this amino acid has been replaced by an arginine residue
which contains a protonated guanidinium functional group. This can form additional ionic and
hydrogen bond interactions with malate that are not possible with lactate. The additional
binding interaction accounts for the selectivity for malate over lactate as the former will have a
much stronger affinity for the active site.

HO CO2
HO CO2
O
O
O Malate NH2
O Malate
O
NH2 N NH2
Gln Arg H

Natural enzyme Mutated enzyme H-bonds

Ionic bond
No interaction with malate Strong interaction with malate

7. A negatively charged oxygen atom is a much stronger hydrogen bond acceptor than an
oxygen without a charge. In the substrate, the carbonyl oxygen has a partial negative charge.
In the transition state, the oxygen atom will have a developing negative charge that will be
more akin to the fully charged oxygen atom in the oxyanion intermediate. Therefore, the
hydrogen bond will be stronger to the transition state.

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Chapter 4

1) A binding site is a hollow or cleft on the surface of a receptor protein into which a chemical
messenger can fit and bind.
A binding region is a specific region of that binding site which is important in the binding
process. It may contain a functional group capable of forming a specific bonding interaction
with a functional group present on the guest molecule or ligand. Alternatively, it may be a
hydrophobic region that can form van der Waals interactions with a hydrophobic region of the
ligand.

2)The possible binding interactions for the functional groups in each molecule are shown as
HBD (hydrogen bond donor), HBA (hydrogen bond acceptor), ionic and vdw (van der Waals
interactions). It should also be noted that van der Waals interactions involving alkyl groups or
alkyl chains are possible, as are interactions for aromatic and aromatic rings.
The following amino acids have side chains which could interact by hydrogen bonding: Ser,
Thr, Tyr, Asn, Gln, Asp and Glu.
The following amino acids have side chains which could interact by ionic interactions: Asp,
Glu, His, Lys, Arg.
The following amino acids have aromatic or heteroaromatic groups in their side chains which
could interact by van der Waals interactions; Phe, Tyr, Try.
The following amino acids contain alkyl side chains which could interact by van der Waals
interactions; Val, Leu. Ile. Met, Pro.
In addition, the peptide links between amino acids can interact with ligands by hydrogen
bonding.

Acetylcholine

HBA
Ionic
O
NMe3
H3C O
HBA

It is also known that three of the four methyl groups fit into hydrophobic pockets and
participate in van der Waals interactions (see also sections 22.5 and 17.14.1). Note also that
the carbonyl oxygen is the stronger HBA of the two oxygen atoms present.

Noradrenaline and adrenaline

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HBD HBD
H HBA H
HBA HBD
O H
H O H HBD HBA H H HBD
HBA
O N O N
HBD H R
HBD H R
vdw HBA vdw Ionic
HBD H HBDH
O O
HBA HBA

The amine group of both nordrenaline and adrenaline can exist as the free base or as the
protonated, ionised form. Note that the nitrogen can act as an HBA in the free base, but not
when it is ionised. The phenolic oxygen atoms are also likely to be relatively weak HBAs.
Further details on the binding interactions of noradrenaline and adrenaline can be found in
sections 17.14.1, 23.8 and 23.9.

Dopamine

HBD HBD
H H HBD
HBA HBA H
O N HBD O N
HBD H H HBD H H HBD
vdw HBA vdw
HBD H HBD H Ionic
O O
HBA HBA

The amine group of dopamine can exist as the free base or as the protonated, ionised form.
Note that the nitrogen can act as an HBA in the free base, but not when it is ionised. The
phenolic oxygen atoms are also likely to be relatively weak HBAs. Further details on the
binding interactions of dopamine can be found in section 17.14.1.

Glycine
Glycine is an amino acid which is more likely to exist as the zwitterion with both the amino
and carboxylic acid groups being ionised. There is no side chain.

HBD HBA HBD HBA

H O HBD H H O
HBD Ionic
N C H N
HBD H O H Ionic O
HBA HBA HBD HBA

Serotonin

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HBD HBD HBD

HBD
H H H HBD
N H N H
HBA
Ionic
HBA HBA
O O
H H
HBD vdw vdw
HBD
N N
H HBD H HBD

The amine group of serotonin can exist as the free base or as the protonated, ionised form.
Note that the nitrogen can act as an HBA in the free base, but not when it is ionised. Note
also that the heterocyclic nitrogen is unlikely to be a good HBA since its lone pair interacts
with the ring's system. Further details on the binding interactions of serotonin can be found
in section 17.14.1.

-Aminobutyric acid

HBD HBA HBD HBA

H O HBD H O
HBD H
N H N Ionic
HBD H O H O
HBA HBA HBD Ionic HBA

Glutamic acid

HBA HBA
HBA HBA
O O O O
HBD HBD Ionic Ionic
H H
O O O O
HBA H HBA HBA Ionic H HBA
HBA N N
H H H H
HBD HBD HBD H HBD
HBD

Glutamic acid is an amino acid where the head group is more likely to be present as a
zwitterion. The side chain can also be ionised to form the glutamate ion.

3) The differences between noradrenaline, isoprenaline, and adrenaline are highlighted

below. Noradrenaline has a primary amine group, whereas the other two structures have
secondary amine groups with N-alkyl substituents.

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H OH H OHH H OHH
HO NH2 HO N CH3 HO N
CH3
CH3
HO HO HO

Noradrenaline Isoprenaline Adrenaline

The difference in receptor selectivities observed between these three compounds indicates
that an N-alkyl substituent has a role to play in receptor selectivity. Increasing the size and
bulk of the N-alkyl substituent results in loss of potency at the -receptor, but an increase in
potency at -receptors. These results indicate that the -adrenoceptor has a hydrophobic
pocket into which a bulky alkyl group can fit, whereas the -adrenoceptor does not (see also
sections [Link] and 23.9.2).

4) In an -helix, the NH and C=O of each peptide link forms hydrogen bonds within the
centre of the helix such that these groups do not have to interact with the hydrophobic centre
of the cell membrane. The -helix also positions the side chains (which are mostly
hydrophobic) to the exterior of the helix where they can interact with the hydrophobic centre
of the cell membrane (see also section 2.2).

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Chapter 5

1) The diagram in the question shows two important hydrogen bonding interactions where
ATP acts both as a hydrogen bond acceptor and a hydrogen bond donor.
empty
HN pocket

H2NOC Thr766
Gln767 H
N
O
O H

H O
H3C N HBD
Leu768 H H
H3C O N
HBA N
N H N 6
S 1 O O O
H3C
Met769 N O P O P O P O
N
O O O O
O
H H
H H
H-bond interaction OH OH

'ribose' pocket

Structure I contains the following groups which could act as HBDs or HBAs. Note that none of
the three nitrogens are likely to be good hydrogen bond acceptors since, in each case, their
lone pair of electrons interacts with a -system.

HBD
H

HBA O N
O HBA

N N
H H
HBD HBD

Based on the binding interaction of ATP, we are looking for a portion of structure I that
contains both a HBD and a HBA. This is the phthalimide ring system 'at the top'. The
molecule could be fitted into the binding site as shown below. Note that an extra hydrogen

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bonding interaction might be possible to Thr766, and that one of aniline rings might be
positioned correctly for the 'ribose' pocket. However, one canot be certain about this, and
molecular modelling experiments would have to be carried out to see whether this is the case
or not.

empty
HN pocket
Gln767 Thr766
H2NOC
H
N
O
O H

H O
H3C N O
Leu768 H
H3C O N

Met769 S N NH
H O
H3C

O
HN

H-bond interaction

'ribose' pocket

2) When the Ras protein is activated, it has an autocatalytic property that catalyses its own
deactivation without the need for any external influence. This takes the form of bound GTP
being hydrolysed to GDP. If this autocatalytic property should be lost, the Ras protein would
remain permanantly activated and this would have serious consequences on cell chemistry
since the Ras protein initiates processes such as cell growth and cell division. Many cancers
have been linked to defective Ras proteins which have lost the ability to deactivate
themselves (see also section 21.6.1).

3) Ras is synthesised in the cytoplasm of the cell and has to become attached to the cell
membrane in order to function properly. The attachment of a long hydrophobic chain means
that the alkyl group can penetrate into the hydrophobic cell membrane and act as a
hydrophobic anchor, holding the Ras protein to the inside surface of the membrane. If the
enzyme was inhibited, the anchor would not be attached to the Ras protein, and the protein
would not become attached to the membrane. As a result, it could no longer act as a signal
protein, and any signal transduction processes involving the Ras protein would be interrupted
(see also section 21.6.1).

4) Signal amplification takes place at the following stages

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a) One adrenaline molecule activating a receptor results in several s subunits being

generated.
b) A single as subunit activating adenylate cyclase is responsible for generating several cyclic
AMP molecules.
c) A single cyclic AMP molecule releases the catalytic subunit of PKA which catalyses i) the
activation of several inhibitors, ii) the deactivation of several glycogen synthase enzymes and
iii) the activation of several phosphorylase kinase enzymes.
d) Each activated phosphorylase kinase enzyme activates several phosphorylase b enzymes.
e) Each phosphorylase a enzyme catalyses the breakdown of several glycogen molecules.

Adrenaline
s
s
-Adrenoceptor Adenylate
cyclase
ATP cAM P

Glycogen Protein kinase A

Inhibitor
synthase
(active) (inactive)
Catalytic
C subunit of
PKA
Glycogen Inhibitor- P Phosphatase
synthase- P (active) (inhibited)
(inactive)

Phosphorylase Phosphorylase
kinase (inactive) kinase- P (active)

Phosphorylaseb Phosphorylasea
(inactive) (active)

Glycogen Glucose-1-phosphate

5) An inhibitor of cAMP phosphodiesterase would prevent cyclic AMP being hydrolysed. As a

result, cyclic AMP would have a longer lifetime leading to increased activity of PKA. This in
turn would lead to increased breakdown of glycogen and an increase in glucose-1-phosphate
production.

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6) The natural enzyme is activated by a serine-threonine kinase which catalyses the

phosphorylation of serine and threonine side chains. Thus, the side chain alcohol of serine
would be phosphorylated as shown.

O O
H H Protein H H
N kinase A N

ATP
OH O

Serine P
O O
O

This can have a profound effect on tertiary structure. The alcohol of serine participates in
hydrogen bonding with other hydrogen bonding groups. Phosphorylation introduces ionic
groups which will form ionic bonds with other ionic groups in the protein leading to a change
in conformation that activates the enzyme. Deactivation occurs when the phosphate groups
are hydrolysed to give back the original alcohol groups. The enzyme then returns to its
original inactive conformation.
In the genetically engineered enzyme, the serine residues are replaced with glutamate
residues (-CH2CH2CO2-). The carboxylate groups are ionised and so the molecule does not
need to become phosphorylated to become active. The glutamate residues form the same
ionic interactions as the phosphate groups and the enzyme is inherently active. Moreover,
there is no way of removing the charge and the enzyme remains permanantly active.

7) Tyrosine kinases catalyse the phosphorylation of the phenol group of tyrosine, but not the
alcohol groups of serine and threonine. This suggests that the active site for a tyrosine kinase
contains a hydrophobic region that can interact with the aromatic ring of tyrosine through van
der Waals interactions or interactions. Since the side chains of serine and threonine do
not contain an aromatic ring, they are not bound so effectively. Therefore, they do not act as
substrates.

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H H
N
Protein
N
N O O O HN Protein

N N O P O P O P O
HO O
O O O O

H H Tyrosine
H residue
H
OH OH

ATP Mg
Tyrosine kinase

H H
N

N N
O O Protein
O P O P O HN Protein
N N
O O O
O O
O
H H P
O
H H O
OH OH
Phosphorylated
ADP tyrosine residue

8) The activation of growth factor receptors involves dimerisation. Antibodies are Y-shaped
molecules where the tip of each arm of the Y binds to a particular target. As a result, an
antibody can act as a bidentate ligand. Consequently, one antibody could bind to two
different receptors, resulting in the dimerisation and activation of the growth factor receptor in
the absence of the natural ligand.

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Chapter 7

1) The structures of isoleucine and valine are as follows.

H H
H2N CO2H H2N CO2H

H3C
CH3 H3C CH3

Isoleucine Valine

Isoleucine has a larger side chain than valine, and so there is less space available in the
active site of COX-1 than there is in the active site of COX-2. Drugs can be designed that
take advantage of this difference such that they fit into the active site of COX-2, but not the
active site of COX-1.

2) The reaction catalysed by acetylcholinesterase on acetylcholine is the hydrolysis of the ester to

produce acetic acid and choline. With neostigmine, the corresponding reaction would be the following:
Me2N O NMe3 Me2N OH HO NMe3
O +
O
Neostigmine
In fact, this does not happen and a stable complex with the enzyme is formed. Following the mechanism
through, serine acts as a nucleophile and a nucleophilic substitution reaction takes place on the urethane
with loss of the phenol group. However, once this has occurred, serine is 'capped' with a stable urethane
group which is resistant to hydrolysis.

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Stage 1 Stage 2
H
: :
O H O
:N :N
NH NH
MeHN C OAr

MeHN O :O:
Ar

:
O
Physostigmine
-ArOH

Stage 3 Stage 4

O O
H N :N
NH NH
: :

MeHN C O Ar MeHN C O Ar
H
:O: : O:
:
:

+H2O

Hydrolysis
VERY SLOW

O O H
:N :N
NH NH
MeHN O
Stable carbamoyl
intermediate

Full details of this process are described in section [Link]

3) A transition-state inhibitor is a drug that mimics the transition state for an enzyme-catalysed reaction.
Such a drug should bind more strongly than either the substrate or the product. As a result, it should be a
potent inhibitor.
The enzyme-catalysed hydrolysis of the peptide bond between Phe or Pro should involve the enzyme
using a nucleophilic group to form a bond to the carbonyl group, resulting in the intermediate shown.

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ENZ

Nu

ENZ
H CO2H H CO2H
Nu
N N
H2N H2N
H H
O
OH

The transition state for this stage should resemble the intermediate more than the starting material, and
so drugs mimicking the transition state should have characteristics also seen in the intermediate. The
similarities in structure I to the intermediate are highlighted in colour below.

extra methylene
group

O O
H H Me
C Me
O N N O
H H Me
OH
tetrahedral centre

Note the presence of the tetrahedral centre bearing the alcohol group - also present in the intermediate.
Note also that there is an extra methylene group between this tetrahedral centre and proline. This is
necessary if the inhibitor is to be stable to the enzyme-catalysed reaction. Further details regarding the
design of this inhibitor can be found in sections [Link] and [Link]
An IC50 6500 nM means that the concentration of inhibitor required to inhibit the enzyme by 50% is 6500
nanomolar.

4) It is proposed that the binding interactions between an enzyme and a substrate are optimal during the
transition state of the enzyme-catalysed reaction. This is a reasonable proposition since the speed and
effectiveness of a catalysed reaction depends crucially on how much the catalyst stablises the transition
state. The more stable the transition state, the lower the activation energy. This, in turn, results in a faste
rate of reaction, which explains why binding interactions play and important role in an enzyme's function
as a catalyst. Therefore, it is more important that enzymes form their strongest interactions with ligands a
the transition state of the reaction, rather than to the substrate or the product. Indeed, strong interactions
with substrate or product are likely to be detrimental since it could result in a slow 'turnover' with substrate
and product spending too much time in the active site.

5) In both cases, the enzyme-catalysed process is stalled. 5-Azacytidine and 5-fluoro-2'-deoxycytidine

react with the enzyme to form structures I and II respectively. In the normal enzyme mechanism, the final
stage involves loss of a hydrogen from structure III to form a double bond within the ring, resulting in
cleavage of the C-S bond linking the structure to the enzyme. This cannot occur in structures I or II. In

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structure II, this mechanism would require the loss of a highly unstable F +. In structure I, one could draw
mechanism involving the lone pair of the nitrogen, but this would involve the nitrogen gaining a positive
charge which is not favoured.

H H H H H H
N N N
Me Me
Me
N N N F N H

H H O N H
O N O N
S-Enz S-Enz S-Enz
R R R

I II III

6) The following table shows the values necessary for both the Michaelis Menten and Lineweaver-Burk
plots in the absence of inihibitor.

Substrate concentration [S] (mol dm-3)

Initial rate (J) (mol dm-3 s-1)
1/(substrate concentration) 1/[S] (mol-1 dm-3)
1/Initial rate (1/J) (mol-1 dm3 s)

[S] J 1/[S] 1/J

0.05 28.6 20 0.035

0.10 51.5 10 0.0194
0.25 101 4 0.0099
0.50 141 2 0.0071
1 172 1 0.0058

The Lineweaver-Burk plot has 1/initial rate (1/J) on the y-axis and 1/substrate concentration (1/[S]) on the
x-axis. This should give a straight line having an intercept of 0.00400 on the y-axis and a slope of
0.00155.
Therefore, the maximum rate of reaction = 1/intercept = 250.2 mol dm -3 s-1

KM = slope x (maximum rate of reaction) = 0.387 mol dm -3

The maximum rate of reaction is achieved at high substrate concentration.
KM is the Michaelis constant and corresponds to the substrate concentration at which the initial rate of
reaction is half of Jmax.

A Michaelis Menten plot of the maximum rate of reaction versus substrate concentration
shows a curve where the line is approaching a maximum plateau, but has not yet reached it.
Therefore, any attempt to define the maximum rate of reaction from this kind of plot can only
be an estimate. Since we need to know the maximum rate of reaction in order to define KM,

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the value of KM will also be inaccurate. The Lineweaver-Burk plot gives a straight line and
allows us define the maximum rate of reaction and KM more accurately.
The Lineweaver-Burk plot gives a straight line and allows us define the maximum rate of reaction and KM
more accurately.

The table for the experiment carried out in presence of 4nM inhibitor is as follows:

Substrate concentration [S] (mol dm-3)

Initial rate J (mol dm-3 s-1)
1/(substrate concentration) 1/[S] (mol-1 dm-3)
1/Initial rate 1/J (mol-1 dm3 s)

[S] J 1/[S] 1/J

0.05 10 20 0.1
0.10 20 10 0.05
0.20 35.1 5 0.0285
0.40 62.5 2.5 0.0160
0.833 100 1.2 0.01

The Lineweaver-Burk plot in the presence of the inhibitor should give a straight-line plot
crossing the y-axis at the same point as the Lineweaver-Burk plot in the absence of
inhibitor. As the lines cross the y-axis at the same point, this indicates competitive
inhibition. The slope of the line in the presence of inhibitor is steeper than the line in the
absence of inhibitor.
As the lines cross the y-axis at the same point, this indicates competitive inhibition. The
slope of the line in the presence of inhibitor is steeper than the line in the absence of inhibitor.
The slope of the line in the presence of inhibitor is steeper than the line in the absence of inhibitor.

Slope in the presence of inhibitor = 0.00477

Maximum rate of reaction = 250.3
KM(app) = 1.19

alpha = KMapp/KM = 1.19/0.387 = 3.075

Therefore Ki = [I]/(alpha -1) = 1.93

7) Analogue I is less active than the original quinazoline as there is no nitrogen to participate in the
hydrogen-bonding network involving water and two tyrosine residues. Moreover, the additional hydrogen
atom would clash with the water molecule and displace it. Therefore, there are fewer binding interactions
for analogue I, making it a weaker inhibitor.

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Steric H HO-Tyr
N
clash O
H H
HO-Tyr
NHR
Analogue I

Analogue II has a nitrile substituent which will also displace the water molecule. However, the nitrile group
can form a hydrogen-bonding interaction directly to one of the tyrosine residues. This binding interaction
must be stronger than the original hydrogen-bonding network involving the quinazoline structure.

N HO-Tyr
C N

NHR
Analogue II

8) The reaction catalysed by cytidine deaminase is as follows and includes an intermediate where an OH
group has been added to form a tetrahedral centre. The OH group is provided by the conserved water
molecule present in the active site.

NH2 NH2 O
Cytidine OH Cytidine
N deaminase HN deaminase HN

O N O N O N
Ribose Ribose Ribose

A possible mechanism is as follows;

H
Enzyme Enzyme
H
O
H NH2 H Nu Nu
NH2 NH2
H O O
HN H H
N HN

O N O N O N
Ribose Ribose Ribose

- NH3 HN

O N
Ribose

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The proton provided in the mechanism is likely to be provided by an amino acid residue
such as histidine.
The proton provided in the mechanism is likely to be provided by an amino acid residue such
as histidine.

The enzyme-catalysed reaction mechanism carried out on zebularine will create the structure
below, which serves as a transition-state analogue and enzyme inhibitor. A transition-state
analogue is an effective inhibitor as it is believed that the transition state of an enzyme-
catalysed reaction mechanism is bound more strongly than either the substrate or the
product. Although a transition state is a highly unstable species, it is believed that it bears
more of a similarity to the reaction intermediate than to the substrate or product. Therefore, a
transition-state analogue should contain a tetrahedral centre and relevant binding groups. In
this case, the OH group can form crucial hydrogen-bonding interactions and is orientated in a
similar manner to the normal reaction intermediate. Unlike the usual reaction intermediate,
however, the transition-state analogue is stable as there is no leaving group available to allow
the formation of the carbonyl group.

H
OH
HN

O N
Ribose

The transition state analogue formed from zebularine.

3,4-Dihydrozebularine lacks the C=N bond within the heterocyclic ring, which means that an
enzyme-catalysed reaction is not possible with the conserved water molecule. Therefore, the
structure binds without any alteration and no transition-state analogue is formed. The
structure binds more weakly as there is no OH group present to form an additional hydrogen-
bonding interaction.

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CHAPTER 8

1) The three molecules are very similar to each other. Structures I and II differ from
acetylcholine in having amine and ethyl groups respectively instead of a methyl group.

O O O
NMe3 NMe3 H3C NMe3
H3C O H2N O O

Acetylcholine I II
One might expect structure II to be active since a methyl and ethyl group are relatively similar
to each other. Both are hydrophobic groups that can interact with a hydrophobic region of a
binding site by van der Waals interactions. In contrast, the NH2 group is polar and is more
likely to interact by hydrogen bonding with a polar region of a binding site. The fact that
structure I is active and structure II is inactive suggests that it is not the type of binding that is
crucial here, but the sizes of the different groups. The methyl and amino groups are similar in
size, whereas the ethyl group is larger. If the space available in the binding site is limited,
structure II may not fit due to the larger ethyl group. Further details can be found in sections
22.5-22.7.

2) The inactive metabolite contains a methyl ether instead of a phenol. This indicates that the
phenol is an important binding group when isoprenaline interacts with the adrenergic
receptor. For example, the hydrogen atom of the phenol may act as a hydrogen bond donor
to a corresponding hydrogen bond acceptor in the binding site. This interaction is no longer
possible for the inactive metabolite. Another possibility is that the phenolic oxygen acts as a
hydrogen bond acceptor and that the methyl group in the metabolite prevents this interaction
due to its size and bulk (see also sections 14.2.6 and 23.10.3). However, a phenolic oxygen
is a relatively weak HBA, and so it is more likely that the phenol serves as an HBD.

H OHH H OHH
HO N CH3 MeO N CH3

CH3 CH3
HO HO

Isoprenaline Inactive metabolite

3) This question is related to question 3 in Chapter 4. Larger and bulkier N-alkyl groups result
in selectivity for the -adrenoceptors (see also section 23.10.3).

4) Both molecules contain the identical moiety shown in red.

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O N H OH
H OH H HO NH2

HO
Propranolol Noradrenaline

The carbon bearing the alcohol group is an asymmetric centre that has the same
configuration in each molecule. This is demonstrated by redrawing propranolol as follows:

H OH H
O N

Propranolol

Therefore, it is possible for this moiety in both molecules to form similar interactions with the
receptor. However, the aromatic systems are different and so different interactions are
possible which can lead to different induced fits. This can account for propranolol acting as
an antagonist rather than as an agonist.
Propranolol is likely to show -adrenergic selectivity due to the fact that it has a bulky N-alkyl
substituent (compare question 3 above and section 23.11.3).

5) There are clear structural similarities between dopamine and noradrenaline.

H OH
HO NH2 HO NH2

HO HO
Dopamine Noradrenaline

Therefore, dopamine is likely to have similar binding interactions with its receptor. Taking this
argument further, strategies that lead to antagonists for adrenergic receptors might also work
in designing antagonists for the dopamine receptor.
Replacing the catechol ring system of noradrenaline with a naphthalene ring resulted in
adrenergic antagonists, so similar tactics with dopamine might also be successful. The
following structures would be worth investigating.

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NH2 O N O NH2
H

The first structure is a straight replacement of the catechol ring of dopamine with a
naphthalene ring. The other two structures are based on the adrenergic antagonist
propranolol, where the alcohol and/or N-alkyl groups have been removed.
Since all these structures lack the side chain alcohol, they are unlikely to bind to adrenergic
receptors.

6) It is worth considering the interactions of estradiol and raloxifene with the estrogen
receptor (Box 8.2) in order to answer this question.

His 524

Asp351
Me OH H
H N
H Side O His 524
chain
Glu353
H H Glu353 O
H OH
O
Hydrophic skeleton H
H2O
O
S
Arg394
Arg394
Oestradiol
Raloxifene
Both estradiol and raloxifene contain functional groups that interact through hydrogen
bonding to the amino acids Glu-353, Arg-394, and His-524. Both molecules have
hydrophobic skeletons that position these groups correctly and match the hydrophobic nature
of the binding site. Estradiol is an agonist, whereas raloxifene is an antagonist. This is due to
the extra interaction with Asp-351 that is possible for raloxifene.
Turning now to tamoxifen, this molecule is also hydrophobic and of a similar size to the
above, allowing it to fit the hydrophobic binding site. It does not have the phenol or alcohol
functional groups present in estradiol or raloxifene, but it does have a group that can interact
with Asp-351 in the same way as raloxifene. Therefore, it binds as an antagonist.

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Asp351
H
Me2N
O

Tamoxifen

7) Although tamoxifen itself is an antagonist, its metabolite is an agonist. This is because it

has lost the group that is so crucial for antagonist activity (the side chain containing the
amine). It also contains a phenol group which can mimic the phenolic group of estradiol (see
above Q6).

Asp351 Asp351
H
Me2N
HO
O

Glu353
Glu353

H O Metabolite
Tamoxifen

Arg394
Arg394

8)
The data required to create Schild plots are the following:

Normorphine and naloxone

[I] dose ratio log[I] 1/dose ratio log(1/dose ratio)

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1 x 10-6 0.0018 -6 555.6 2.75

1 x 10-7 0.0178 -7 56.2 1.75
3.162 x 10-8 0.1122 -7.5 8.91 0.95

Metkephamid and naloxone

[I] dose ratio log[I] 1/dose ratio log(1/dose ratio)

3.16 x 10-7 0.0562 -6.5 17.8 1.25
1x 10-7 0.1585 -7 6.31 0.8
3.162 x 10-8 0.7943 -7.5 1.26 0.1

Met-enkephalin and naloxone

[I] dose ratio log[I] 1/dose ratio log(1/dose ratio)

3.16 x 10-7 0.0398 -6.5 25.13 1.4
1x 10-7 0.2512 -7 3.98 0.6
3.162 x 10-8 0.8913 -7.5 1.12 0.05

The Schild plots have the following intersections with the x-axis. These correspond to the
values for pA2.
Normorphine and naloxone -8.36
Metkephamid and naloxone -7.61
Met-enkephalin and naloxone -7.50
The values of pA2 are similar for metkephamid and Met-enkephalin indicating that these have
similar target selectivities.

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Chapter 19

1) Penicillin G could be converted to 6-APA by a process similar to that described for the
conversion of cephalosporins to 7-ACA (Fig 19.37)

H H H H H 1. H2O
R1 N S R1 N R1 N
PCl5 ROH -R1CO2H
7
6-APA
O N Cl OR 2. Deprotection
O O O
CO2SiMe3
Imino chloride Imino ether

Protecting
group
Modified diagram

The synthesis of ampicillin could be carried out as follows:

ZHN H
Cl
H H ZHN H H H H
H2N S O N S
Me
N O
Acid chloride N Deprotection
O Me
CO2H O
CO2H
7-APA

H2N H H H H
N S
Me
O N Me
O
CO2H
Ampicillin

Note that it would be necessary to protect the primary amine present in the acid chloride.
Otherwise the molecule would couple with itself.

2)
Replacing valine with alanine

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H Cys SH
H2N
H H H
R N S
R OH CO2H Ala
Me
H2N O N
O Biosynthesis
O
CO2H CO2H

Replacing valine with phenylalanine

H Cys SH
H2N
H H H
R N S
R OH CO2H Phe
Ph
H2N O N
O Biosynthesis
O
CO2H CO2H

Replacing valine with glycine

H Cys SH
H2N
H H H
R N SH
R OH CO2H
Gly O
H2N N
O Biosynthesis
O
CO2H CO2H

Since glycine has no side chain it is not possible to form the thiazolidine ring. This might be
too much of a variation even if it was possible to modify the biosynthesis, and so the structure
shown is highly speculative.

Replacing valine with lysine

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H Cys SH
H2N
H H H
Lys R N S
R OH CO2H
(CH2)4NH2 NH2
H2N O N
O Biosynthesis
O
CO2H CO2H

Replacing cysteine with serine

H Ser OH
H2N
H H H
R N
R OH CO2H Me Val O
Me
Me
H2N O N
O Biosynthesis Me
O
CO2H CO2H

3) The enzymes involved in the biosynthetic pathway must be specific in identifying cysteine
and valine as the amino acid building blocks for penicillin. There are probably pockets in the
enzyme active site that accept the side chains for valine and cysteine, but not other side
chains.

4) The sulphonamides act as competitive inhibitors of the enzyme, dihydropteroate

synthetase. They do this by mimicking one of the natural substrates for the enzyme, namely
para-aminobenzoic acid.

O OH
1
R HN S O H2N C
NHR2 O
Sulphonamides
para-Aminobenzoic acid

Procaine is a local anaesthetic containing an ester group which can be hydrolysed by

esterases in the blood supply. This generates para-aminobenzoic acid. The levels of para-
aminobenzoic acid produced in the body now rise and can compete more effectively against
sulphonamide for the enzyme's active site. Thus, the effectiveness of sulphonamide
decreases.

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CH3
CH3
N
Esterases HO
O N
C NH2
CH3 C NH2 OH
O
O CH3
Procaine para-Aminobenzoic acid

5) The structure can be viewed as a penicillin/cephalosporin hybrid because it contains

features of cephalosporins (shown in red) which are good for cephalosporin activity.

NH2
H H H
N S
O
O N
O
O
CO2H CH3
Penicillin analogue

In theory, a similar mechanism of action might occur, resulting in a more active penicillin.

NH2 NH2
H H H H H H
N N S O
S
O HO
O N O N
O O CH3
O
CO2H CH3 Enz-Nu CO2H

Enz-Nu
However, it is likely that this structure will be too unstable to be of any clinical use. The
bicyclic ring system is already strained and introducing the double bond to the five-membered
ring will increase strain even further, more so than in the six-membered ring of a
cephalosporin. This suggests that the mechanism shown will occur in the presence of any
sort of nucleophile, including water.

6) The ethoxy groups will act as bigger steric shields and increase the protection of the
susceptible b-lactam ring. This will increase the stability of the molecule to chemical and
enzymatic hydrolysis.
Unfortunately, the ethoxy groups will also hinder the molecule from acting at the
transpeptidase enzyme, and it is likely to have poor activity.

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7) The bicyclic ring system in penicillins consists of a beta-lactam ring fused with a 5-
membered ring. This results in greater ring strain in the beta lactam ring of penicillins than in
a monocyclic beta lactam ring. A 6-membered ring is more stable than a 5-membered ring
and so the fusion of a beta-lactam ring with a six-membered ring in cephalosporins
introduces less ring strain. Therefore, one would expect the beta lactam ring in
cephalosporins to be less strained and less reactive than in penicillins. In turn, one would
expect the cephalosporins to be less active. On the other hand, cephalosporins have a good
leaving group that encourages ring opening of the beta-lactam ring (Fig. 19.35).

8)

H OMe H H OMeH
N S N S
7
S O 3 S O N O CF3
N O NH2
C O C
O
O CO2H O
CO2H
Cefoxitin Cefoxitin analogue
The analogue contains a trifluoromethyl group in place of an amino group. The trifluoromethyl
group is a good electron-withdrawing group and would make the trifluoroacetate moiety a
good leaving group.

electron withdrawing
O CF3
C
O
Good leaving group

This is good for the mechanism of action of cephalosporins (see Fig. 19.35). However, it also
makes the group a good leaving group when it comes to ester hydrolysis, either chemically or
enzymatically. Therefore, the compound is likely to have too short a lifetime in the body to be
useful.

9) The structure of bacampicillin is as follows:

H2N H H H H
N S
Me Me O
O C
N Me R= O O Me Bacampicillin
O
CO2R

The mechanism by which it is transformed to ampicillin is as follows:

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Esterase

Penicillin O O O Penicillin O O Penicillin O

C C H C
O O O OH
H
H + CH3CHO
+
acetaldehyde
H
O O CO2 + CH3CH2OH
H
O

10)
No carbonyl group
No carboxylic O
O acid group O F CO2H
F F CO2H F CO2H
H N N
N N N Me
N N HN F
HN HN H
H2N No nitrogen
Me
F

I II III IV

Structure I lacks the carboxylic acid that is normally present at position 3 of fluoroquinolones.
This group forms important binding interactions with the topoisomerase enzyme and so its
absence will result in a drop in activity.
Structure II lacks the carbonyl group that is normally present at position 4. This group is
important in binding to DNA and so its absence is detrimental to activity.
Structure III lacks the nitrogen atom normally present at position 1 and would be expected to
have lowered activity.
Structure IV has all the important binding groups and substituents. Therefore, it should have
the highest activity.

11)
O O O
F F F
Cl CH2(CO2Et)2 CH(CO2Et)2 a) H+/D CH2CO2Et

Mg(OEt)2 b) H+/EtOH
Cl Cl Cl Cl Cl Cl

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O O O
F CO2Et F CO2Et F CO2Et
HC(OEt)3

Ac2O CHOEt NH2 CH Base

Cl Cl F Cl Cl -HCl Cl N
HN
F
F
F F

O O
F CO2H F CO2H
H+

N H H
Cl NH
N N
HN
F HN
H F
H

F F

© Oxford University Press, 2017.