58 Drug-Receptor Interaction

Types of Binding Forces partial charges. When a hydrogen atom

bearing a partial positive charge bridges
Unless a drug comes into contact with two atoms bearing a partial negative
intrinsic structures of the body, it can- charge, a hydrogen bond is created.
not affect body function. A van der Waals’ bond (B) is
Covalent bond. Two atoms enter a formed between apolar molecular
covalent bond if each donates an elec- groups that have come into close prox-
tron to a shared electron pair (cloud). imity. Spontaneous transient distortion
This state is depicted in structural for- of electron clouds (momentary faint di-
mulas by a dash. The covalent bond is pole, δδ) may induce an opposite dipole
“firm”, that is, not reversible or only in the neighboring molecule. The van
poorly so. Few drugs are covalently der Waals’ bond, therefore, is a form of
bound to biological structures. The electrostatic attraction, albeit of very
bond, and possibly the effect, persist for low strength (inversely proportional to
a long time after intake of a drug has the seventh power of the distance).
been discontinued, making therapy dif- Hydrophobic interaction (C). The
ficult to control. Examples include alky- attraction between the dipoles of water
lating cytostatics (p. 298) or organo- is strong enough to hinder intercalation
phosphates (p. 102). Conjugation reac- of any apolar (uncharged) molecules. By
tions occurring in biotransformation al- tending towards each other, H2O mole-
so represent a covalent linkage (e.g., to cules squeeze apolar particles from
glucuronic acid, p. 38). their midst. Accordingly, in the organ-
Noncovalent bond. There is no for- ism, apolar particles have an increased
mation of a shared electron pair. The probability of staying in nonaqueous,
bond is reversible and typical of most apolar surroundings, such as fatty acid
drug-receptor interactions. Since a drug chains of cell membranes or apolar re-
usually attaches to its site of action by gions of a receptor.
multiple contacts, several of the types of
bonds described below may participate.
Electrostatic attraction (A). A pos-
itive and negative charge attract each
other.
Ionic interaction: An ion is a particle
charged either positively (cation) or
negatively (anion), i.e., the atom lacks or
has surplus electrons, respectively. At-
traction between ions of opposite
charge is inversely proportional to the
square of the distance between them; it
is the initial force drawing a charged
drug to its binding site. Ionic bonds have
a relatively high stability.
Dipole-ion interaction: When bond
electrons are asymmetrically distribut-
ed over both atomic nuclei, one atom
will bear a negative (δ–), and its partner
a positive (δ+) partial charge. The mole-
cule thus presents a positive and a nega-
tive pole, i.e., has polarity or a dipole. A
partial charge can interact electrostati-
cally with an ion of opposite charge.
Dipole-dipole interaction is the elec-
trostatic attraction between opposite
Lüllmann, Color Atlas of Pharmacology © 2000 Thieme
All rights reserved. Usage subject to terms and conditions of license.
 Drug-Receptor Interaction 59

Drug + Binding site Complex

+ – + –
D 50nm D

Ion Ion Ionic bond

δ+ δ– – δ+ δ– –
D 1.5nm D

Dipole (permanent) Ion

δ+ δ– δ– δ+ δ– δ–
D 0.5nm D
δ+ δ+

D = Drug Dipole Dipole Hydrogen bond

A. Electrostatic attraction

δδ+ δδ–
δδ– δδ+
D D δδ– δδ+
δδ+ δδ–

Induced
transient
fluctuating dipoles

B. van der Waals’ bond

δ+
"Repulsion" of apolar
particle in polar solvent (H2O)
δ− apolar
polar
Phospholipid membrane

Apolar
acyl chain

Insertion in apolar membrane interior Adsorption to

apolar surface

C. Hydrophobic interaction

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

All rights reserved. Usage subject to terms and conditions of license.