human biochemistry and pathology to drive the design of drug-like molecules engineered
to fit precisely into targets of drug action (druggable targets).
A Drug as a Composite of Molecular FragmentsFor the practical implementation of this idealistic strategy, drug molecules are concep-
tualized as being assembled from biologically active building blocks (biophores) that
are covalently “snapped together” to form an overall molecule. Thus, a drug molecule
is a multiphore, composed of a fragment that enables it to bind to a receptor (phar-
macophore), a fragment that influences its metabolism in the body (metabophore), and
one or more fragments that may contribute to toxicity (toxicophores). The drug
designer should have the ability to optimize the pharmacophore while minimizing the
number of toxicophores. To achieve this design strategy, these fragments or building
blocks may be replaced or interchanged to modify the drug structure. Certain building
blocks (called bioisosteres), which are biologically equivalent but not necessarily
chemically equivalent, may be used to promote the optimization of the drug’s biological
properties.
DRUG DESIGN: THE HUMANITARIAN APPROACH
In traditional medicine there are two major therapeutic approaches to the treatment of
human disease: surgical and medical. Surgical procedures are labour intensive and time
demanding; they help a limited number of individuals, one at a time, mostly in rich or
developed nations. Medical therapy, on the other hand, is based on drug molecules and
thus has the capacity to positively influence the lives of more people, often over a
shorter time frame. Medical therapeutics offer hope in both developed and developing
parts of the world—hopefully to rich and poor alike.
After public health measures (e.g., safe drinking water, hygienic disposal of waste
water), the discovery of drugs has had one of the largest beneficial effects on human
health. Penicillin has saved countless lives through the effective treatment of devastat-
ing infectious diseases. Before penicillin, a diagnosis of meningococcal meningitis was
invariably a death sentence. Penicillin reduced bacterial meningitis to a treatable disor-
der. Similarly, drugs for the treatment of high blood pressure have substantially reduced
the impact of this “silent killer” that leads to myocardial infarction (heart attack) or
cerebral infarction (stroke).
It can be awe-inspiring to witness the effects of a seemingly trivial amount of
drug. The panic-stricken child who cannot breathe because of an asthma attack gets
prompt relief from the inhalation of a mere 100 micrograms of salbutamol sulphate.
Uncontrolled and potentially life-threatening seizures (status epilepticus) in a young
adult are quickly brought under control with the intravenous administration of 2 mg of
lorazepam. The terrified older adult with crushing chest pain from a myocardial infarc-
tion gains rapid relief from 8 to 10 mg of morphine. Drugs are truly amazing molecules.
A medicinal chemist can help thousands or even millions of people with a carefully
designed new drug molecule. The practice of science is a very human activity; medicinal
chemistry is a humanitarian science.
8 MEDICINAL CHEMISTRY