Download The macromolecular sites of action through which drugs

The macromolecular sites of action through which drugs
mediate their effects are usually proteins. An understanding
of what forces are responsible for the binding of drugs to
proteins may be obtained by first considering what forces
drive protein folding since these 2 processes share many
common characteristics.
The observed tertiary or quaternary structure of proteins is
in large part a consequence of the hydrophobic effect. This
means that proteins tend to bury hydrophobic residues in
the core, while exposing hydrophilic residues to the exterior.
Hydrophilic groups, if located at the interior are almost
invariably paired with other hydrophilic groups to form
hydrogen bonding interactions which compensate for the
desolvation of these polar functions
In this context, the ligand binding clefts in proteins often expose
hydrophobic residues to solvent, and may contain partially desolvated
hydrophilic groups that are not paired with complementary hydrogen
bonding residues. These hydrophilic groups in this area are probably
not exposed to sufficient solvent due to the steric constraints of
protein folding.
This means, that structurally, ligand binding pockets are sticky,
representing non-optimally folded portions of the protein, and that
such proteins may be considered as being incompletely folded.
This also means that the interaction of a binding cleft with a
complementary ligand is energetically favourable since this interaction
buries exposed hydrophobic patches and forms favourable
electrostatic contacts with hydrophilic groups that are located within
the binding cleft and are insufficiently exposed to solvent.
Hence, and very importantly, the association of the ligand with the
protein may be viewed as the last step in the protein folding process.
The stability of the protein is consequently increased consequent to
ligand binding.
From an evolutionary standpoint, endogenously, the stability of a
protein is sacrificed in order to create a binding site, and this loss of
stability may be recaptured by binding with an appropriate ligand.
As with protein folding, the principal forces driving drug binding are
thought to be the hydrophobic effect, and electrostatic interactions
which include hydrogen bonding. It has been proposed furthermore,
that the hydrophobic component, which is known to be largely nondirectional, contributes largely to affinity, whereas hydrogen bonding,
because of its highly directional nature, contributes principally to
specificity.