properties in a therapeutically beneficial manner. This is a design method that is lofty
and difficult to attain.
Rational drug design is an iterative process, dependent upon feedback loops and new
information. When the drug designer makes the first prototype molecule, this molecule
becomes a probe with which to test the drug design hypotheses. The molecule can then
be further designed and refined to better improve its ability to dock with the receptor
site and elicit a biological response. This cycle of “design–test–redesign–retest” can go
on for several iterations until the optimized molecule is achieved.
Rational drug design is a very intellectually satisfying activity. The successful ratio-
nal design of a drug is similar to solving a major puzzle using your wits and wisdom.
The macromolecules involved in the disease have been determined; the structures
of these macromolecules have been ascertained using X-ray crystallography and/or
computer-aided molecular design; a small organic molecule capable of binding to the
macromolecule has been cleverly designed; a synthesis for this small organic molecule
has been devised; and biological testing has confirmed the bioactivity of the small
organic molecule.
Despite protestations from the “naysayers” who despondently claim that all drugs are
discovered by serendipity, there is an increasing number of examples that exemplify the
successes and practical utility of rational drug design. Perhaps one of the earliest exam-
ples is the discovery of cimetidine, an H2-antagonist drug used for the treatment of
peptic ulcer disease. Even though the complete structure of the receptor was not fully
appreciated, the careful manipulation of the molecule’s physicochemical properties
(based in part upon an understanding of the underlying histamine molecule) led to the
discovery of cimetidine. More recently, the design of drugs for the treatment of AIDS
has provided superb examples of rational drug design. The HIV virus encodes for a pro-
tease, called HIV-1/PR, that is required for its replication. Using X-ray crystallographic
studies of recombinant and synthetic HIV-1/PR helped to identify the active site of the
protein. Next, a complex between the HIV-1/PR protein and a prototype inhibitor was
also structurally solved using X-ray crystallography. These structural studies greatly
facilitated the process of rational drug design, ultimately leading to six rationally
designed therapeutics: amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and
lopinavir.
As evidenced by the aforementioned examples, structural chemistry is front and
center in enabling rational drug design. Molecular modeling, also called quantum phar-
macology, has been instrumental to many of the advances in rational drug design. Some
cynics are quick to pontificate that there are no drugs that have been designed by com-
puters. Strictly speaking, this is true; likewise, no drugs have been designed by a
nuclear magnetic resonance spectrometer. Computers do not design drugs, people do.
However, computers are immensely valuable in advancing and progressing the art and
science of rational drug design.
3.2.5.3 Role of Quantum Pharmacology in Rational Drug Design
Quantum pharmacology calculations have, are, and will continue to revolutionize ratio-
nal drug design. Until the dawning of the 20th century, it was believed that all reality was
eminently describable through Newton’s Laws. These laws, the foundation of Newtonian
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 119