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3

Basic Principles of Drug Design III

Designing drug molecules to fit receptors

3.1 OVERALL STRATEGY: THE MULTIPHORE

METHOD OF DRUG DESIGN

The aim of this book is to provide a conceptual framework for medicinal chemistry.
Chapter 1 dealt with the properties necessary to transform a molecule into a drug-like
molecule. Chapter 2 described the properties that determine whether a macromolecule
could be a receptor. It is now necessary to develop a method of designing drug molecules
to fit into receptor molecules. The multiphore methodof drug design is such a method.
The multiphore method conceptualizes a drug as being constructed in a modular fash-
ion from bioactive subunits, or biophores. Since a drug is invariably composed of many
biophores, it is a multiphore. The most important biophore within the drug structure is the
pharmacophore, the subset of atoms within the drug that permits energetically favorable
binding to the receptor site with the elucidation of a subsequent beneficial biological
response. Other portions of the molecule determine the metabolic and toxicological prop-
erties of the drug; these are the metabophoresandtoxicophores, respectively.
In the design of drugs using the multiphore method it is important to remember that
there is nothing special about any particular drug molecule. A successful drug molecule
is merely a collection of “hetero-atom rich” functional groups appropriately positioned
on the three-dimensional space of a hydrocarbon framework in a fixed geometrical rela-
tionship that enables a desirable interaction with a receptor macromolecule. When the
medicinal chemist knows the bioactive zoneof the receptor macromolecule, he or she
identifies multiple functional groups, usually within 15 Å of each other, within that
bioactive zone. The selection of these receptor-based functional groups is a crucial step.
For example, if the receptor zone were within the brain, it would be inadvisable to select
many charged (anionic or cationic) functional groups, since a drug capable of binding
to these receptor-based functional groups via electrostatic interactions would be too
polar to diffuse across the blood–brain barrier and enter the brain.
Next, complementary functional groups capable of energetically favorable intermolec-
ularinteractions with the receptor-based functional groups are selected. These comple-
mentary functional groups will ultimately form part of the drug that is being designed