Lead Modification

Principles of Drug design

Lead modification : Drug design and

development
1. Identification of the active part : the
pharmacophore
2. Functional group modification
3. SAR relationships
4. Privileged structures and drug-like molecules
5. Structure modifications to increase potency
and therapeutic index

1. Identification of the active part : the

pharmacophore

analgesic and
addictive

3-4 times
more potent
analgesic and
addictive

Less potent
analgesic and less
addictive

3200 times
more potent
analgesic and
less addictive

2. Functional group modification

R=NH2
carbutamide
Antibacterial
Antidiabetic

Antidiabetic

3. Structure Activity Relationship- SAR

4. Previleged structures and drug like

molecules

Benzodiazepines

5. Structure modifications to increase

potency and therapeutic index
a)
b)
c)
d)
e)

Homologation
Chain branching
Ring chain transformations
Bioisosterism
Combinatorial Chemistry

5.a.Homologation

5.b.Chain Branching

Promethazine antispasmodic and antihistaminic activities predominate

Promazine reduced antispasmodic and anti-histaminic activities,
enhanced sedative and tranquilizer activities
Trimeprazine reduced tranquilizing activity with increased anti-pruritic activity

5.c.Ring Chain Transformations

Reasons :
Increase lipophilicity
Decrease metabolism
Contraining the groups into a particular favorable
conformation

5.d.Bioisosterism
Bioisosteres are substituents or groups that
have chemical or physical similarities, and
which produce broadly similar biological
properties.
Types
i. Classical
ii. Non-classical

i. Classical Bioisosteres
Classical bioisosteres are functional groups that possess similar valence
electron configurations.
For example,
oxygen and sulphur are both in column VI of the periodic table; thus, a
thioether (-C-S-C-) is a classical bioisosteric substitution for an ether (-CO-C-) functional group.

ii. Non-classical bioisosteres

Non-classical bioisosteres are functional groups with dissimilar
valence electron configurations;
for instance, a tetrazole moiety may be used to replace a
carboxylate since many biological systems are unable to
differentiate between these two very structurally distinctive
functional groups.

Ring replacement as bioisosteric

approach

Pharmacological Effects of
Bioisosterism
Structural holding other functionalities
where particular geometry, then size, shape
and hydrogen bonding is important
Pharmacokinetics for ADME of the drug,
where lipophilicity, pKa and hydrogen bonding
are important
Metabolism blocking or aiding metabolism

5.e.Combinatorial Chemistry
Chemical libraries comprising of building
blocks to give a diverse array of molecules
with a common scaffold
Advantages
Carried out on a solid (polymeric) support to aid
isolation and purification by simple flitration and
washing.
Example : peptide synthesis