Uncompetitive inhibitorsare believed to form a complex with the enzyme–
substrate complex. The formation of this complex prevents the substrate
reacting to form its normal product(s).
7.3.2 Irreversible inhibition
Irreversible inhibitors may be classified for convenience asactive site directed
inhibitorsandsuicideorirreversible mechanism based inhibitors (IMBIs). They
bind to the enzyme by either strong non-covalent or strong covalent bonds.
Inhibitors bound by strong non-covalent bonds will slowly dissociate, releasing
the enzyme to carry out its normal function. However, whatever the type of
binding, the enzyme will resume its normal function once the organism has
synthesized a sufficient number of additional enzyme molecules to overcome the
effect of the inhibitor.
Active site directed inhibitorsare compounds that bind at or near to the active
site of the enzyme. These inhibitors usually form strong covalent bonds with
either the functional groups that are found at the active site or close to that site.
Since these groups are usually nucleophiles, the incorporation of electrophilic
groups in the structure of a substrate can be used to develop new inhibitors
(Table 7.3). This approach may also be used to enhance the action of a known
inhibitor. Most of the active site directed irreversible inhibitors in clinical use
were not developed from a substrate. They were obtained or developed by other
routes and only later was their mode of action discovered. For example, aspirin,
Table 7.3 Examples of the electrophilic groups used to produce active site directed inhibitorsNucleophilic group
of enzyme (E) Electrophilic group Product
E–NH 2 Anhydrides RCOOCOR Amides RCONH–E
Ketones>C¼O Imines>C¼NE
Arenesulphonyl halides RSO 2 X Arenesulphonamides RSO 2 NH–EE–COOH Epoxides O
RHydroxyesters RCH(OH)CH 2 CO 2 –Ea-Haloacetates X-CH 2 CO 2 Half esters ̄O 2 CCHCO 2 –EE–OH Phosphoryl halides (RO) 2 PO(X) Phosphates (RO) 2 OPO–E
Carbamates RNHCOOR Carbamates RNHCOO–EE–SH a-Haloesters X-CH 2 CO 2 R Sulphides ROCOCH 2 –S–E
a-Haloacetates X-CH 2 CO 2 Sulphides ROCOCH 2 –S–E
Epoxides ORHydroxy sulphides RCH(OH)CH 2 –S–E140 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS