- The receptor should be present in the tissues in quantities commensurate with
established receptor concentrations (10–100 pmol/g). - The binding of a drug to its receptor should be saturable, with a binding equilibrium
constant in the nanomolar range. However, it must be borne in mind that saturability
is not identical with specificity. - Binding kinetics should be proportional to the rate of the in vivo response and should
yield an equilibrium constant equal to the dissociation rate constant divided by the
association rate constant. - Wherever applicable, binding should be stereospecific; but the fulfilment of this cri-
terion is not absolute proof that the site being investigated is a receptor. Opiates, for
instance, may bind stereospecifically to glass-fiber filters. - The receptor should be isolated from an organ or tissue relevant to the disease
process under investigation. Hallucinogen binding to liver tissue, for example, is
unlikely to indicate more than the presence of a metabolizing enzyme. - It is desirable that the order of drug binding to a receptor preparation in a related
series of drugs be the same as the order of their clinical or at least their in vivo
activity. As a check on methodology, nonspecific drugs should be included in such
a series.
Failure to meet even one of these criteria jeopardizes the identification of the receptor.
Even when all of the criteria are fulfilled, extreme caution in data interpretation is still
mandatory.
2.2.1 What Is a Druggable Target?Drug receptors are macromolecules, but not all macromolecules are drug receptors. As
discussed above, a macromolecule should be “worthy and capable of being targeted for
drug design.” Such a macromolecule is typically a protein that is intimately connected
with a disease process but is not crucial to a wide range of other normal biochemical
processes. A macromolecule that can be usefully attacked for purposes of drug design
is termed a druggable target.
2.3 DEFINITIONS OF DRUG–RECEPTOR BINDING
INTERACTIONS
In molecular terms, the activity of drugs is initiated by their atomic-level interaction
with a receptor. Since the association of small molecules (e.g., drugs) with macromol-
ecules (e.g., receptors) is promoted and stabilized by intermolecular interactions, an
understanding of the nature of chemical bonds and intermolecular interactions is of
great interest to the medicinal chemist. As discussed earlier, covalent and noncovalent
bonds are both based on electronic interactions but differ greatly in their stabilities,
which are expressed in terms of bond dissociation energies. Table 2.1 summarizes the
various types of intermolecular interactions and their average energies. These interac-
tions are discussed in greater detail in sections 2.3.1–2.3.7 below. Although there is no
direct correlation between drug–receptor binding energy and drug potency, the energy
values provide an approximate estimate of the ease of formation, the ease of disruption,
and the relative strengths of various intermolecular interaction types.
RECEPTORS: STRUCTURE AND PROPERTIES 69