Fundamentals of Medicinal Chemistry

OH

R R R

O O

Nu

Enz

Oxidation

(Oxidoreductase)

Michael type

addition of Enz-Nu

Michael type

addition of Enz-Nu

Elimination

(Lyase )

R R R

O O

Nu

Enz

F O *

*

Oxidation

(Oxidoreductase)

Nucleophilic

addition of Enz-Nu

*

NuEnz

OH

OH O

O

O

O O

Br Br

Enz

O

O

O

Nu-Enz

Enz

O

Haloenol lactone

Hydrolysis

(Serine protease)

Nucleophilic

substitution of the

halogen by Enz-Nu

*

Figure 7.5 Examples of the reactions to enhance or form the electrophilic centres*of suicide

inhibitors and their subsequent reaction with a nucleophile at the active site of the enzyme. The

general structures used for the enzyme–inhibitor complexes are to illustrate the reactions; the

enzyme ester groups may or may not be present in the final complex

Thea,bunsaturated carbonyl compounds and imines formed in this manner

react by a type of Michael addition with nucleophilic groups (Nu), such as the

OH of serine residues, the SH of cysteine residues and thev-NH 2 of lysine

residues, frequently found at the active sites of enzymes.

X Nu X− X

H+

Enz Enz Nu

Enz Nu

Enz Nu X

−

X¼O, S or NR

7.3.3 Transition state inhibitors

The substrate in an enzyme catalysed reaction is converted to the product

through a series of transition state structures (Appendix 7). Although these

transition state structures are transient, they bind to the active site of the enzyme

and therefore must have structures that are compatible with the structure of the

142 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS