Medicinal Chemistry

While most drugs do not covalently attach themselves to their receptors, a few do.
Penicillin (2.3), one of the most important antibacterial agents of the past century, func-
tions via the formation of covalent bonds. It acts by acylating a bacterial transpeptidase
enzyme that is vital to cell-wall synthesis within the bacterium; by structurally disrupt-
ing the cell wall, penicillin leads to death of the bacterial cells. Bonds to receptor sites
are also formed by antiparasitic agents that inactivate the thiol enzymes of a parasite
through bonding of a heavy metal (e.g., As, Bi, Sb) to the sulphur atoms in the enzyme’s
thiol groups. Finally, antitumor nitrogen mustards alkylate the amino groups of guanine
bases in DNA and crosslink the two strands of the DNA double helix, preventing gene
replication and transcription.

2.3.2 Ionic Bond Interactions

Ionic bonds are formed between ions of opposite charge. Their electrostatic interaction
is very strong:

with a bonding energy (E) that can approach or even exceed the energy of a covalent
bond. Ionic bonds are ubiquitous and, since they act across long distances, play an
important role in the actions of ionizable drugs. The interaction between a negatively
charged carboxylate and a positively charged ammonium is a prototypic example of an
ionic interaction. The use of charged groups within a drug molecule can be used to
influence the pharmacokinetic properties of the molecule. For example, incorporating
highly polar charged groups, such as sulphonates, will decrease a drug’s half-life by
increasing the rate of renal excretion. Also, charged groups can be used to preclude a
drug molecule from traversing the blood–brain barrier.

2.3.3 Dipole–Dipole Interactions

Molecules in which there is a partial charge separation between adjacent atoms or func-
tional groups can interact either with each other (via a dipole–dipoleinteraction) or
with ions. Dipole moments are bond moments resulting from charge differences and the
distance between charges within a molecule; they are vectorial quantities and are
expressed in Debye units (about 10–20esum, or electrostaticunits per meter). Linear
group moments (as in p-dichlorobenzene) can cancel one another out; nonlinear ones
(e.g.,m-dichlorobenzene) are added vectorially. Since so many functional groups have

RECEPTORS: STRUCTURE AND PROPERTIES 71

E=e 1 e 2 /Dr (2.1)