Drug Design

OPTIMIZING TARGET INTERACTIONS

 Lead X-ray
SAR Crystal
Compound crystallography
The eventual drug should have a good selectivity and level of
activity for its target, and have minimal side effects
It should be easily synthesized and chemically stable
Itshould be non-toxic and have acceptable pharmacokinetic
properties
 In this chapter, we concentrate on design strategies that can be
used to optimize the interaction of the drug with its target in order to
produce the desired pharmacological eff ect; in other words, its
pharmacodynamic properties
Binding role of alcohols and
phenols
Alcohols and phenols are functional groups which are commonly
present in drugs and are often involved in hydrogen bonding
The oxygen can act as a hydrogen bond acceptor, and the
hydrogen can act as a hydrogen bond donor
Binding role of aromatic rings

Aromatic rings are planar, hydrophobic structures, commonly

involved in van der Waals interactions with flat hydrophobic regions
of the binding site.
An analogue containing a cyclohexane ring in place of the
aromatic ring is less likely to bind so well, as the ring is no longer flat.
The axial protons can interact weakly, but they also serve as buffers
to keep the rest of the cyclohexane ring at a distance
Binding role of amines

Amines are extremely important functional groups in medicinal

chemistry and are present in many drugs.
They may be involved in hydrogen bonding, either as a hydrogen
bond acceptor or a hydrogen bond donor
 In many cases, the amine may be protonated when it interacts with
its target binding site, which means that it is ionized and cannot act
as a hydrogen bond acceptor.
However, it can still act as a hydrogen bond donor and will form
stronger hydrogen bonds than if it was not ionized
Binding role of amides

Amides are likely to interact with binding sites through hydrogen

bonding
The carbonyl oxygen atom can act as a hydrogen bond acceptor
and has the potential to form two hydrogen bonds
The nitrogen cannot act as a hydrogen bond acceptor because
the lone pair interacts with the neighbouring carbonyl group as
described earlier
The amide group is planar and does not rotate because of its partial
double bond character
Binding role of quaternary
ammonium salts
Quaternary ammonium salts are ionized and can interact with
carboxylate groups by ionic interactions
Another possibility is an induced dipole interaction between the
quaternary ammonium ion and any aromatic rings in the binding
site
This allows an interaction between the slightly negative faces of the
aromatic rings and the positive charge of the quaternary
ammonium ion. This is also known as a cation interaction .
Binding role of carboxylic acids

The carboxylic acid group is reasonably common in drugs.

It can act as a hydrogen bond acceptor or as a hydrogen bond
donor
Alternatively, it may exist as the carboxylate ion. This allows the
possibility of an ionic interaction and/or a strong hydrogen bond
where the carboxylate ion acts as the hydrogen bond acceptor
Binding role of esters

Esters are susceptible to hydrolysis in vivo by metabolic enzymes

called esterases .
This may pose a problem if the lead compound contains an ester
that is important to binding, as it means the drug might have a short
lifetime in vivo
Esters that are susceptible to metabolic hydrolysis are sometimes
used deliberately to mask a polar functional group, such as a
carboxylic acid, alcohol, or phenol, in order to achieve better
absorption from the gastrointestinal tract.
Once in the blood supply, the ester is hydrolysed to release the
active drug. This is known as a prodrug strategy
Binding role of alkyl and aryl halides

Alkyl halides involving chlorine, bromine, or iodine tend to be

chemically reactive as the halide ion is a good leaving group.
As a result, a drug containing an alkyl halide is likely to react with
any nucleophilic group that it encounters and become
permanently linked to that group by a covalent bondan alkylation
reaction
 Aryl halides do not act as alkylating agents and pose less of a
problem in that respect.
As the halogen substituents are electron-withdrawing groups, they
affect the electron density of the aromatic ring and this may have
an influence on the binding of the aromatic ring
Isosteres

Isosteres are atoms or groups of atoms which share the same

valency and which have chemical or physical similarities
For example, SH, NH , and CH are isosteres of OH, whereas S, NH,
and CH2 are isosteres of O.
Isosteres can be used to determine whether a particular group is an
important binding group or not by altering the character of the
molecule in as controlled a way as possible
Pharmacophore

Defines the important groups involved in binding

Defines the relative positions of the binding groups
Need to know the active conformation
Structural (2D) pharmacophore

Defines minimum skeleton connecting important binding groups

HO

O MORPHINE
NMe

HO
Important groups for analgesic activity

HO

O MORPHINE
NMe

HO
Important groups for analgesic activity

HO

O MORPHINE
NMe

HO
Analgesic pharmacophore for opioids

HO

N
 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
 HO
HO

O
H3C NMe
NMe
CH3
HO METAZOCINE
MORPHINE
HO

NMe

LEVORPHANOL
3D pharmacophore

Defines relative positions in space of important binding groups

HO

O
NMe

HO
O

Arr

N
O 2.798 A
18.5o
Arr
150o

4.534 A
7.098 A

11.3o
N
 Pharmacophore
r r triangles
tri l

Pharmacophore triangles for dopamine

Variation of substituents
Alkyl substituents

If alkyl groups are interacting with a hydrophobic pocket in the

binding site, then varying the length and bulk of the alkyl group (e.g.
methyl, ethyl, propyl, butyl isopropyl, isobutyl, or t -butyl) allows one
to probe the depth and width of the pocket.
Choosing a substituent that will fill the pocket will then increase the
binding interaction
 Larger alkyl groups may also confer selectivity on the drug.
For example, in the case of a compound that interacts with two
different receptors, a bulkier alkyl substituent may prevent the drug
from binding to one of those receptors and so cut down side effects
Aromatic substituents

If a drug contains an aromatic ring, the position of substituents can

be varied to find better binding interactions, resulting in increased
activity
 Changing the position of one substituent may have an important
effect on another.
For example, an electron withdrawing nitro group will affect the
basicity of an aromatic amine more significantly if it is at the para
position rather than the meta position.
At the para position, the nitro group will make the amine a weaker
base and less liable to protonate.
This would decrease the amines ability to interact with ionic binding
groups in the binding site, and decrease activity
Extension of the structure

Lead compounds are capable of fitting the binding site and have
the necessary functional groups to interact with some of the
important binding regions present.
However, it is possible that they do not interact with all the binding
regions available.
For example, a lead compound may bind to three binding regions in
the binding site but fail to use a fourth. Therefore, why not add extra
functional groups to probe for that fourth region? As long as this
does not disrupt important binding interactions that are already
present
 Extension strategies are used to strengthen the binding interactions
and activity of a receptor agonist or an enzyme inhibitor, but they
can also be used to convert an agonist into an antagonist.
This will happen if the extra binding interaction results in a different
induced fit from that required to activate the receptor
Chain extension/contraction
Ring expansion/contraction

Expanding or contracting a ring may put other rings in different

positions relative to each other, and may lead to better interactions
with specific regions in the binding site
Ring variations
Simplification of the structure

Simplification is a strategy which is commonly used on the often

complex lead compounds arising from natural sources.
Once the essential groups of such a drug have been identified by
SAR, it is often possible to discard the non-essential parts of the
structure without losing activity.
Consideration is given to removing functional groups which are not
part of the pharmacophore, simplifying the carbon skeleton (for
example removing rings), and removing asymmetric centres.
 Simpler molecules are often more flexible and can sometimes bind
differently to their targets compared with the original lead
compound, resulting in different effects.
It is best to simplify in small stages, checking that the desired activity
is retained at each stage.
Oversimplification may also result in reduced activity, reduced
selectivity, and increased side effects.
Rigidification of the structure

Flexible molecule with several rotatable bonds that can lead to a

large number of conformations or shapes. One of these
conformations is recognized by the receptor and is known as the
active conformation
The other conformations are unable to interact efficiently with the
receptor and are inactive conformations.
However, it is possible that a different receptor exists which is
capable of binding one of these alternative conformations. If this is
the case, then our model neurotransmitter could switch on two
different receptors and give two different biological responses, one
which is desired and one which is not.
 Incorporating the skeleton of a flexible drug into a ring is the usual
way of locking a conformation
 Locking a rotatable bond into a ring is not the only way a structure
can be rigidified. A flexible side chain can be partially rigidified by
incorporating a rigid functional group such as a double bond,
alkyne, amide, or aromatic ring
Drug Design
OPTIMIZING ACCESS TO THE TARGET
Optimizing hydrophilic/
hydrophobic properties
Drugs which are too polar or too hydrophilic do not cross the cell
membranes of the gut wall easily
They are also likely to have polar functional groups which will make
them prone to plasma protein binding, metabolic phase II
conjugation reactions, and rapid excretion
Very hydrophobic drugs fare no better. If they are administered
orally, they are likely to be dissolved in fat globules in the gut and will
be poorly absorbed. If they are injected, they are poorly soluble in
blood and are likely to be taken up by fat tissue, resulting in low
circulating levels
 Masking polar functional groups to decrease polarity
Molecules can be made less polar by masking a polar functional group
with an alkyl or acyl group

Adding or removing polar functional groups to vary polarity

the antifungal agent tioconazole is only used for skin infections because
it is non-polar and poorly soluble in blood. Introducing a polar hydroxyl
group and more polar heterocyclic rings led to the orally active
antifungal agent fluconazole, with improved solubility and enhanced
activity against systemic infection
 Good in vitro, poor in vivo. Large number of polar groups
 Variation of N-alkyl substituents to vary basicity

pH outside 6 9 tend to be difficult to absorp

Reduce basicity for better absorption
Making drugs more resistant to chemical
and enzymatic degradation
Steric shields
Some functional groups are more
susceptible to chemical and
enzymatic degradation than
others. For example, esters and
amides are particularly prone to
hydrolysis
A common strategy that is used to
protect such groups is to add steric
shields, designed to hinder the
approach of a nucleophile or an
enzyme to the susceptible group
 Metabolic blockers, Removal or replacement of susceptible
metabolic groups
Steric and electronic modifications

procaine is a good, but short-lasting, local anaesthetic because its

ester group is quickly hydrolysed.
Changing the ester group to the less reactive amide group reduces
susceptibility to chemical hydrolysis.
Furthermore, the presence of two ortho -methyl groups on the
aromatic ring helps to shield the carbonyl group from attack by
nucleophiles or enzymes
 Group shifts
Making drugs less resistant to drug
metabolism
Introducing groups that are
susceptible to metabolism is a
good way of shortening the
lifetime of a drug
Prodrugs

Prodrugs are compounds which are inactive in themselves, but

which are converted in the body to the active drug.
They have been useful in tackling problems such as acid sensitivity,
poor membrane permeability, drug toxicity, bad taste, and short
duration of action
Prodrugs to improve membrane
permeability
Esters as prodrugs
 Trojan horse approach for transport proteins
Levodopa is a prodrug for the neurotransmitter dopamine and has been
used in the treatment of Parkinsons disease
Dopamine itself cannot be used as it is too polar to cross the blood
brain barrier. Levodopa is even more polar and seems an unlikely
prodrug, but it is also an amino acid, and so it is recognized by the
transport proteins for amino acids which carry it across the cell
membrane.
Once in the brain, a decarboxylase enzyme removes the acid group
and generates dopamine.
Prodrugs to prolong drug activity
Prodrugs masking drug toxicity and
side effects
Prodrugs to improve water solubility