method can be used to identify the biotoxicface of the molecule (i.e., the toxicophore),
which could then be engineered out of the molecular structure.
Once QSAR calculations have been used to optimize the pharmacodynamic interac-
tions of the drug molecule, the next step is to optimize the pharmacokinetic and phar-
maceutical phases of drug action.
3.5 OPTIMIZING THE LEAD COMPOUND: PHARMACOKINETIC
AND PHARMACEUTICAL PHASES
Once the lead drug molecule has been optimized for the pharmacodynamic phase, it
must next be optimized for the pharmacokinetic and pharmaceutical phases. If a drug
molecule cannot withstand the trip from the gut to the receptor microenvironment, it
makes no difference whether the drug actually binds to the receptor.
Many factors must be taken into consideration when optimizing for the pharmacoki-
netic and pharmaceutical phases. Will the drug be annihilated within the gastrointesti-
nal tract? Will the drug be absorbed? Can the drug molecule be distributed throughout
the body? Will the drug be destroyed in the liver? Will the drug’s half-life be too short,
or too long? Will the drug be excreted too rapidly? If the drug is destined for a brain-
based receptor, can the drug cross the blood–brain barrier?
3.5.1 ADME ConsiderationsWhen optimizing for the pharmacokinetic/pharmaceutical phases, considerations of
ADME (absorption, distribution, metabolism, excretion) are among the most important.
(Sometimes ADME is extended to ADMET because of the inclusion of toxicity.) The
drug designer must optimize the drug so that it can remain structurally intact during its
absorption and distribution. This can be a daunting task, since the body inflicts many
metabolic chemical reactions upon the drug molecule during the processes of absorp-
tion and distribution. Understanding these metabolic reactions is crucial to the contin-
uing optimization of the drug molecule.
3.5.1.1 Overview of Metabolic Reactions Affecting Drug Molecules
The body uses its usual array of chemical reactions to attack the structural integrity of
a drug molecule and to promote its excretion from the body. These reactions can be cat-
egorized into Phase I and Phase II reactions. Phase I transformations (oxidation, reduc-
tion, hydrolysis) initiate the chemical modification, frequently adding functional groups
and increasing polarity; Phase II transformations (conjugations) promote the aqueous
solubility of the drug metabolite so that it may be excreted from the body. A more
detailed delineation of these transformations is as follows:
Phase I transformations:
Oxidations
Oxidation of aliphatic carbon atoms
Oxidation of carbons adjacent to sp^2 hybridized atoms
Oxidation of C=C (alkene) systems
Oxidation of C-O systems
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