Fundamentals of Medicinal Chemistry

active site. Consequently, it has been proposed thatstable compounds with

structures similar to those of these transition state structures could bind to the

active site of an enzyme and act as inhibitors for that enzyme. Compounds that

fulfil this requirement are known astransition state inhibitors. They may act in

either a reversible or irreversible manner.

The structures of transition states may be deduced using classical chemistry

and mechanistic theory. These structures may also be visualized using com-

puters (see Chapter 5). The resultant transition state structure and/or pictures

may be used as the starting point for the design of a transition state inhibitor.

For example, in the early 1950s it was observed that some rat liver tumours

appeared to utilize more uracil in DNA formation than healthy liver. The first

step in the biosynthesis of pyrimidines is the condensation of aspartic acid with

carbamoyl phosphate to form N-carbamoyl aspartic acid, the reaction being

catalysed by aspartate transcarbamoylase (Figure 7.6(a) ). It has been proposed

that the transition state for this conversion involves the simultaneous loss of

phosphate with the attack of the nucleophilic amino group of the aspartic acid on

the carbonyl group of the carbamoyl phosphate (Figure 7.6(b) ). Consequently,

the structure of the experimental anticancer drug, sodium N-phosphonoacetyl-

L-aspartate (PALA, Figure 7.6(c) ), was based on the structure of this transition

state but without the amino group necessary for the next stage in the

CH 2 NH

C

COOH

CH

CH 2

COOH

O

P

O−

O−

O O−

P

O−

O−

O

O

O− P

O−

O

O O−

COOH

COOH

P

−O

O

O CH

NH 2 CH 2

OO−

C

CH

O

NH 2 CH 2

COOH

C

NH

COOH

H++

Aspartate

transcarbamoylase

H 2 O

Aspartic acid

Carbamoyl
phosphate

(a)

N-Carbamoyl aspartic acid (CAA)

NH

O

NH COOH

CH

O

CH 2

C

COOH

CH

NH 2 CH 2

C

H 2 N

COOH

Bond forming

Bond breaking

(b) (c)

Dihydroorotic acid (DHOA)

H 2 N

Figure 7.6 (a) The first step in the biosynthesis of pyrimidines. (b) The proposed transition state

for the carbamoyl phosphate/aspartic acid stage in pyrimidine synthesis. (c) The structure of

sodium N-phosphonoacetyl-L-aspartate (PALA)

DRUGS THAT TARGET ENZYMES 143