opportunity to explore these non-naturally occurring synthetic compounds as potential
lead compounds.
The concept of rational drug design (in contrast to its logical counterpart, irrational
drug design) implies that the disease under consideration is understood at some funda-
mental molecular level and that this understanding can be exploited for purposes of
drug design. Such an understanding would facilitate the design of purely synthetic mol-
ecules as putative drugs. Although this ideal of rational drug design has been pursued
for many years (see section 3.2.5.1 for a historical example), it really only began to
emerge as a viable drug discovery strategy in the last three decades of the 20th century.
3.2.5.1 Bromides for Epilepsy: An Early Example of “Rational” Drug Design
Bromine was discovered in seawater in 1826. Recognizing its chemical similarity to
iodine, French physicians immediately exploited it as an iodine alternative for the treat-
ment of numerous conditions, including syphilis and thyroid goitre. Although no bene-
ficial effects were reported for either bromine or its potassium salt, their widespread use
persisted and eventually the depressant effect of potassium bromide on the nervous
system, so-called ivresse bromurique, was recognized. However, it was a report in the
German literature concerning bromide’s ability to induce impotence and hyposexuality,
rather than ivresse bromurique, which lead to its discovery as an anticonvulsant.
In 1857, Sir Charles Locock, the physician accoucheur to Queen Victoria, ascrib-
ing to the then prevalent view that epilepsy arose from excessive sexuality, introduced
bromide as an anaphrodisiac to suppress the supposed hypersexuality of epileptics.
The bromide salts (e.g., potassium bromide, sodium bromide) were administered in
substantial doses, ranging from 0.3 g/day in children to a staggering 14 g/day in
adults. Although side effects had been considerable (and included psychoses and
serious skin rashes), bromides were successful in 13 of the 14 patients treated. On
11 May 1857, at a meeting of the Royal Medical and Chirurgical Society, Locock
proudly reported his success in treating “hypersexual” epilepsies with bromides. He
argued that logical and rational drug development had finally been achieved for the
time: epilepsy arises from excessive sexuality; potassium bromide suppresses sexual-
ity; therefore, potassium bromide successfully treats epilepsy. In principle it seemed
like a major success of rational drug design. In reality, it was little more than yet
another serendipitous discovery, since hypersexuality has absolutely nothing to
do with epilepsy. Regardless of the flawed reasoning, bromides were a major step
forward in the treatment of epilepsy and their use persisted until the introduction of
phenobarbital in 1912.
3.2.5.2 A Modern Definition of Rational Drug Design
Thankfully, the science of rational drug design has improved substantially since Victorian
times. In modern times, rational drug design is defined as a method whereby a disease
is understood at a molecular level such that the biological macromolecules involved in
the disease process have been identified, purified, characterized, and have had their
three-dimensional structure elucidated, thereby enabling the intelligent and insightful
engineering of organic molecules to dock to that macromolecule and alter its functional
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