Fundamentals of Medicinal Chemistry

3.2 Stereochemistry and drug design

It is now well established that the shape of a molecule is normally one of the

most important factors affecting drug activity. Consequently, the overall shape

of the structure of a molecule is an important consideration when designing an

analogue. Some structural features impose a considerable degree of rigidity on a

structure, whilst others make the structure more flexible. Other structures give

rise to stereoisomers, which can exhibit different potencies, types of activity and

unwanted side effects (see Table 2.1). This means that it is necessary to pharma-

cologically evaluate individual stereoisomers and racemates. Consequently, one

must take into account all these stereochemical features when proposing struc-

tures for potential leads and analogues. However, the extent to which one can

exploit these structural features will depend on our knowledge of the structure

and biochemistry of the target biological system.

3.2.1 Structurally rigid groups

Groups that are structurally rigid are unsaturated groups of all types and

saturated ring systems (Figure 3.2). The former includes esters and amides

as well as aliphatic conjugated systems, aromatic and heteroaromatic ring

systems. The binding of these rigid structures to a target site can give infor-

mation about the shape of that site as well as the nature of the interaction

between the site and the ligand. Furthermore, the fact that the structure is

rigid means it may be replaced by alternative rigid structures of a similar size

and shape to form analogues, which may have different binding characteris-

tics and possibly as a result a different activity or potency (see sections 2.3

and 4.3.2).

C

CH

N

CH 3

C

C

H

H
H

C

H H

Selegiline (MAO inhibitor)

N

H

H

O

O

C

H

CH 3 H

CH 3

CH 3

CH 3

Acetylcholine

CH 3

CH 3

CH 3

CH 3

N

H

H

O

O

C

1-Ethoxycarbonyl-2-

trimethylaminocyclopropane

(Acetylcholine mimic)

Figure 3.2 Examples of structural groups that impose a rigid shape on sections of a molecule.

The shaded areas represent the rigid sections of the molecule

STEREOCHEMISTRY AND DRUG DESIGN 59