1.1.4 Structural Fragments of Drug Molecules:
Interchangeable BioisosteresA drug molecule may be conceptualized as a collection of molecular fragments or build-
ing blocks. The most important fragment is the pharmacophore, with the functional
groups of the pharmacophore being displayed on a molecular framework composed of
metabolically inert and conformationally constrained structural units. These structural
units may be an alkyl chain, an aromatic ring, or a section of peptide chain backbone.
When designing or constructing a drug molecule, one can thus pursue a fragment-by-
fragment building block approach. In conceptualizing this approach, one sees that certain
molecular fragments, although structurally distinct from each other, may behave identi-
cally within the biological milieu of the receptor microenvironment. These structurally
distinct yet biofunctionally equivalent molecular fragments are referred to as bioisosteres.
(A bioisosteric drug is a drug molecule that arises from the replacement of either an atom
or a group of atoms with a biologically equivalent atom or group of atoms to create a new
molecule with pharmacological properties similar to those of the parent molecule.)
There are many examples of bioisosteric substitutions. For example, a drug that con-
tains a sulphonate functional group (SO 3 – ) within its pharmacophore may interact with
a receptor via an electrostatic interaction, whereby the negatively charged sulphonate
group interacts with a positively charged ammonium within the receptor. In designing
analogs of this drug, it would be possible to replace the sulphonate with a bioisosteri-
cally equivalent carboxylate group. The carboxylate group would be able to interact
electrostatically with the ammonium functional group in a fashion analogous to the
sulphonate moiety. This bioisosteric substitution would bring additional advantages
such as a prolonged half-life for the drug molecule since the carboxylate is less polar
than the sulphonate and is thus less susceptible to rapid renal excretion. There are many
other examples of bioisosteric substitutions. For example, H- may be replaced by F-; a
carbonyl group (C=O) may be replaced by a thiocarbonyl group (C=S); a sulphonate
may be replaced by a phosphonate.
Bioisosteric substitutions may be categorized as classicalornon-classical. Classical
bioisosteres are functional groups that possess similar valence electron configurations.
For example, oxygen and sulphur are both in column VI of the periodic table; thus, a
thio–ether (-C-S-C-) is a classical bioisosteric substitution for an ether (-C-O-C-) func-
tional group. Non-classical bioisosteres are functional groups with dissimilar valence
electron configurations; for instance, a tetrazole moiety may be used to replace a car-
boxylate since many biological systems are unable to differentiate between these two
very structurally distinctive functional groups (see figure 1.5).
A consideration of bioisosterism is important in drug design. A systematic explo-
ration of bioisosteres when constructing drug molecules as collections of molecular
fragments enables a rigorous structural consideration of varying pharmacophores and
their properties during the pharmaceutical, pharmacokinetic, and pharmacodynamic
phases of drug action.
1.1.5 Structural Properties of Drug MoleculesA drug molecule is a collection of molecular fragments held in a three-dimensional
arrangement that determines and defines all of the properties of the drug molecules.
DRUG MOLECULES: STRUCTURE AND PROPERTIES 21