of ways of identifying a potential lead compound, including rational drug design, random
high throughput screening, and focused library screening. Once a lead compound has
been successfully identified, it must be optimized. Optimization may be achieved using
quantitative structure–activity relationship (QSAR) studies. Synthetic organic chem-
istry is a crucial component of this step in drug development. The process of drug
design must be validated by actually making and testing the drug molecule. An ideal
synthesis should be simple, be efficient, and produce the drug in high yield and high
purity.
Once the basics of drug design are in place, the drug designer next focuses upon the
task of connecting a drug–receptor interaction to a human disease—this is the goal of
the second phase. For example, how does one design a drug for the treatment of cancer
or Alzheimer’s disease? This phase of drug design requires an understanding of bio-
chemistry and of the molecular pathology of the disease being treated.
The human body normally moves through time with its various molecular processes
functioning in a balanced, harmonious state, called homeostasis.When disease occurs,
this balance is perturbed by a pathological process. For a drug molecule, the goal is to
rectify this perturbation (via the action of molecular therapeutics) and to return the body
to a state of healthy homeostasis. Logically, there are many approaches to attaining this
therapeutic goal. First, one may ask what are the body’s normal inner (endogenous)
control systems for maintaining homeostasis through day-to-day or minute-to-minute
adjustments? These control systems (for example, neurotransmitters, hormones,
immunomodulators) are the first line of defense against perturbations of homeostasis.
Is it possible for the drug designer to exploit these existing control systems to deal with
some pathological process? If there are no endogenous control systems, how about
identifying other targets on endogenous cellular structures or macromolecules that will
permit control where endogenous control has not previously existed? Alternatively,
instead of pursuing these endogenous approaches, it is sometimes easier simply to
attack the cause of the pathology. If there is a harmful microorganism or toxin in the
environment (exogenous), then it may be possible to directly attack this exogenous
threat to health and inactivate it. Accordingly, this phase of drug development, which
connects the drug–receptor interaction to human disease, may be divided into three
logical approaches:
- Know how to manipulate the body’s endogenous control systems (chapters 4–6).
- Know how to manipulate the body’s endogenous macromolecules (chapters 7 and 8).
- Know how to inactivate a harmful exogenous substance (chapter 9).
A full understanding of the three steps of phase 1 and the three approaches of phase 2
will enable the researcher to design drugs.
DRUG DESIGN: A PRACTICAL APPROACH
This book aims to put forth a strategy to facilitate the insightful design of new chemical
entities as therapies for human disease—a strategy that will foster the ability to sit down
in front of a blank computer screen and draw molecules that may help cure the various
maladies that afflict humankind. This strategy uses a molecular-level understanding of
GENERAL MOLECULAR PRINCIPLES OF DRUG DESIGN 7