thus more readily excreted in the urine or bile. The enzymes that catalyze conjugations are
transferases such as glucuronosyltransferase, sulfotransferase, glycine N-acyltransferase,
and glutathione S-transferase. The conjugation reactions normally target hydroxyl,
carboxyl, amino, or thiol groups. Glucuronidation is the most common conjugation
method. There are four classes of glucuronide metabolites: O-, N-, S-, and
C-glucuronides. Sulphate conjugations occur less frequently.
Figure 3.7 depicts several of these reactions.
3.5.1.3 Vulnerability of Molecular Building Blocks to Metabolic Reactions
When designing and optimizing a drug molecule within the multiphore conceptualiza-
tion, it is important to remember that the drug molecule is constructed from molecular
building blocks that add function and structure to the molecule. It is important that the
vulnerability of each of these building blocks to metabolic attack be appreciated during
the drug design process. This section lists the major molecular building blocks and
briefly outlines their susceptibility to metabolism.
Alkanes. Alkyl functional groups tend to be metabolically nonreactive and to be
excreted unchanged. Therefore, alkanes can be used to build the framework of a mole-
cule or as lipophilic functional groups. There are a few exceptions to the rule of alkanes
being metabolically inert. Rarely, a linear alkyl group will be oxidized in a process that
is catalyzed by a mixed-function oxidase enzyme. When this occurs, it does so either at
the end of the hydrocarbon chain or adjacent to the final carbon (the “omega-minus-one
carbon”). The metabolism of butylbarbital is a good example of this (see figure 3.8).
Cycloalkanes. Cycloalkanes are conformationally restricted alkanes. Three rings are
employed in drug design: cyclopropane, cyclopentane, cyclohexane (the latter two are
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 149Figure 3.7 Examples of drug metabolism by oxidative and reductive pathways.