Medicinal Chemistry

planar compounds sometimes have the capacity to insert themselves within nucleic
acids, potentially inducing cancer-causing changes.
When contemplating the effect of drug conformation on drug–receptor interactions, one
must not forget that the receptor macromolecule also undergoes changes in its molecular
geometry, as postulated by the Koshland induced-fit hypothesis (see chapter 2). Owing to
the enormously more complex nature of macromolecular structure, less is known about
such changes. Many examples of conformational changes of enzymes during their reac-
tions with substrates have been well studied and described in the literature, including those
of carboxypeptidase, dihydrofolate reductase, and acetylcholinesterase (see section 7.1.2).

1.3.2 Steric Effects on Drug–Receptor Interactions

During the geometrical interaction between a drug and its receptor, steric factors fre-
quently emerge as extremely important considerations. At times, a large, bulky sub-
stituent appended to a fragment within a drug molecule may physically impede the
geometry of interaction between a drug and its receptor. Historically, the first attempt
to include steric effects in relationship studies between the structure and pharmacolog-
ical activity of a molecule was the Taft steric parameter(ES). This parameter was
defined as the difference between the logarithm of the relative rate of the acid-
catalyzed hydrolysis of a carboxymethyl-substituted compound, and the logarithm of
the rate of hydrolysis of methyl acetate as a standard:

where X is the molecule or molecular fragment in question to which a carboxy-methyl
group has been attached. With some corrections suggested by other authors,EShas
proven to be useful in quite a few structure–activity correlations.
Another classical measure of the molecular geometry of substituents is the Verloop
steric parameter. This is calculated from bond angles and atomic dimensions—primarily
the lengths of substituent groups and several measures of their width. Trivial as this may
sound, the consideration of molecular “bulk” is an important and often neglected factor
in making multiple quantitative correlations of structure and pharmacological activity.
Balaban et al. (1980) devised several related methods that are still in use today.

1.4 STEREOCHEMICAL PROPERTIES OF DRUG MOLECULES

Since drugs interact with optically active, asymmetric biological macromolecules such as
proteins, polynucleotides, or glycolipids acting as receptors, many of them exhibit stereo-
chemical specificity. This means that there is a difference in action between stereoisomers
of the same compound, with one isomer showing pharmacological activity while the other
is more or less inactive. In 1860, Louis Pasteur was the first to demonstrate that molds and
yeasts can differentiate between (+)- and (−)-tartarates, utilizing only one of the two isomers.
Therefore, complementarity between an asymmetric drug and its asymmetric receptor is
often a criterion of drug activity. The effects of highly active or highly specific drugs depend
more upon such complementarity than do those of weakly active drugs. Occasionally,
the stereoselectivity of a drug is based on a specific and preferential metabolism of one
isomer over the other, or on a biotransformation that selectively removes one isomer. Such

36 MEDICINAL CHEMISTRY

ESX=logKXCOOCH 3 −logKCH 3 COOCH 3 (1.3)