1.1.3 Structural Fragments of a Drug Molecule: Pharmacophore,
Toxicophore, MetabophoreAs previously defined, a drug molecule consists of functional groups displayed in a
defined geometric array that permits a binding interaction with a receptor during the
pharmacodynamic phase of drug action. The three-dimensional arrangement of atoms
within a drug molecule that permits a specific binding interaction with a desired recep-
tor is called the pharmacophore. The atoms that constitute the pharmacophore are a
subset of all the atoms within the drug molecule. The pharmacophore is the bioactive
face of the molecule and is that portion of the molecule that establishes intermolecular
interactions with the receptor site. (In principle, the term pharmacophore is an abstract
concept. A pharmacophore is the assembly of geometric and electronic features
required by a drug molecule to ensure both an optimal supramolecular interaction with
its target receptor and the elicitation of a biological response. The term pharmacophore
does not represent a single real molecule but a portion of a molecule. It is incorrect to
name a structural skeleton, such as a phenothiazine or a prostaglandin, as a pharma-
cophore. It is correct, however, to regard a pharmacophore as the common structural
denominator shared by a set of bioactive molecules; the pharmacophore accounts for
the shared molecular interaction capabilities of a group of structurally diverse drug
molecules toward a common target receptor.)
Depending on which face it puts forward, a single drug molecule may interact with
more than one receptor and thus may have more than one pharmacophoric pattern. For
example, one bioactive face of acetylcholine permits interaction with a muscarinic
receptor, while another bioactive face of acetylcholine permits interaction with a nicotinic
receptor (section 4.2). Similarly, the excitatory neurotransmitter glutamate may bind to
a range of different receptors, such as the NMDA and AMPA receptors (section 4.7),
depending upon the pharmacophoric pattern displayed by the glutamate molecule
toward the receptor with which it is interacting.
The other portions of the drug molecule that are not part of the pharmacophore
constitutemolecular baggage.The role of this molecular baggage is to hold the func-
tional group atoms of the pharmacophore in a fixed geometric arrangement (with
minimal conformational flexibility) to permit a specific receptor interaction while
minimizingbothinteractions with toxicity-mediating receptors andthe metabolic
(via liver) and rapid excretion (via kidney) problems associated with the pharmaco-
kinetic phase.
Two other less frequently discussed fragments of a drug molecule are the toxicophoreand
themetabophore. Conceptually, these two types of fragment are analogous to the pharma-
cophore. (Collectively, pharmacophores, toxicophores, and metabophores may be referred
to as biophores.) The toxicophore is the three-dimensional arrangement of atoms in a
drug molecule that is responsible for a toxicity-eliciting interaction. If a drug molecule
has multiple toxicities arising from several undesirable interactions, then it may possess
more than one toxicophore. From the perspective of drug design, if a toxicophore
does not overlap with the pharmacophore in a given drug molecule, then it may be pos-
sible to redesign the molecule to eliminate the toxicity. However, if the pharmacophore
and toxicophore are congruent molecular fragments, then the toxicity is inseparable from
the desired pharmacological properties. The metabophore is the three-dimensional
DRUG MOLECULES: STRUCTURE AND PROPERTIES 19