Some Principles of Rational Structure-Based Drug Design

Eric Burks and Michael Wester
University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

Drug design has traditionally been a random process of biological and chemical
experimentation, typically screening large libraries for drugs that interfere
with the normal progress of a disease.  This is an expensive proposition, both
in time and in money, so a more "rational" approach has long been desired.  In
the last few years, structure-based drug design has come into its own with its
most notable success a pill announced in late 2000 that has so far proved in
clinical trials to be 90% effective in treating patients suffering from chronic
myeloid leukemia.  In addition, the side effects from this drug are less than
that produced by aspirin.  Chronic myeloid leukemia, one of the four major
varieties of adult leukemia (cancer of the blood cells), had only been
treatable previously by bone marrow transplants, a procedure that has a 20%
mortality rate just for the operation.

In this talk, we will present some of the basic principles of structure-based
drug design.  "Structure-based" implies that we know the three dimensional
structures of the proteins (or some of the proteins) involved in the disease,
usually from x-ray diffraction experiments.  These proteins interact by
latching together ("docking" in biomedical parlance), which is effectively a
process of energy minimization.  The objective is to design a small molecule
that will block the undesired protein interaction.

Currently, the drug design process is to identify lead compounds, either by
biologic assays or computationally searching chemical data banks.  The lead
compounds are then refined so that they possess certain key properties:

(1) high affinity (that is, they dock well with the target protein),
(2) low molecular weight (making them easy to synthesize),
(3) long serum half life (the medicine does not decay rapidly),
(4) easy to administer (orally or intravenously),
(5) low toxicity (we want the cure to be not worse than the disease!).

As possible drugs are designed, it is necessary to test them in vitro on
cellular cultures.  Those that seem promising then proceed through in vivo
(animal) and finally human clinical trials as part of the process leading to
routine clinical use.