to render the molecule less like a naturally occurring peptide. Next, this segment is then
rebuilt isosteric fragment by isosteric fragment, gradually replacing each portion of the
molecule in a stepwise fashion. For example, the amide bond may be replaced by a
bioisosterically equivalent amide bioisostere. In this fashion, an equivalent but non-
peptidic organic molecule drug eventually emerges.
An alternative approach is a little less plodding and perhaps a little more elegant. The
three-dimensional structure of the peptide is determined using either theoretical (molec-
ular mechanics, molecular orbital calculations) or experimental (X-ray crystallographic,
NMR spectroscopic) methods. Next, an educated guess (hopefully based on some exper-
imental data) is made to suggest which portion of the peptide is the pharmacophore. The
geometries of the functional groups within the pharmacophore are then measured from
the theoretical and experimental studies of the peptide’s geometry and conformation. For
example, these data may show that the peptide pharmacophore contains a carboxylate
group located 4.6 Å from a hydroxyl group, which in turn is 5.1 Å from a phenyl group.
Using these precise data, databases of known organic molecules are then computation-
ally searched to identify an organic molecule with similar functional groups held in the
same position in three-dimensional space. Hopefully, this will yield a non-peptidic but
bioactive organic molecule drug.
3.2.3.2 Other Endogenous Drug Lead Platforms: Carbohydrates, Nucleic Acids
Although peptides have been studied the most extensively, there are other endogenous
molecules within the human body worthy of exploitation as drug discovery platforms.
These include nucleic acids, lipids, and carbohydrates, which are discussed in detail in
chapter 8. These molecules share the same potential strengths and weaknesses as do
peptides. Likewise, there is a need to develop small organic molecules as mimetics of
these other endogenous molecules. Although not as clearly defined as peptidomimetic
chemistry, ultimately, “nucleotidomimetic” or “carbohydromimetic” chemistries may
eventually emerge as new design strategies for lead compound identification.
3.2.4 Lead Compound Identification from Exogenous
Sources: EthnopharmacologyIn section 3.2.3, the utility of naturally occurring molecules, which are endogenous to
the human body, was discussed as a source of bioactive lead compounds. An alternative
is to exploit molecules that are endogenous to other life forms (animal or plant) but do
not naturally occur within humans. Such molecules would be classed as exogenous
from the perspective of drug design for humans.
Historically, plant-based natural products have been a source of useful drugs. The anal-
gesic opiates come from the poppy plant. Digitalis for congestive heart failure was first
isolated from the foxglove plant. Various antibiotics (penicillin) and anticancer agents
(taxol) are derived from natural product sources. There are numerous other examples.
There is good reason to be optimistic about the potential future usefulness of such
exogenous compounds as a continuing source of potential lead compounds. With many
thousands of years of trial-and-error by evolution on her side, Mother Nature is a vastly
superior experimentalist to any mere human organic chemist. Insect evolution has per-
mitted the biosynthesis of anticoagulant molecules to ensure that a bite will provide a
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 115