Medicinal Chemistry

2.3.1 Covalent Bond Interactions

Although very important in traditional organic chemistry, covalent bonds are less
important in drug–receptor binding than noncovalent interactions. It is generally not
desirable to have a drug covalently linked to its receptor, since such an interaction
would persist for a long period of time. Such prolonged interactions tend to lead to dif-
ficulties with lengthy drug half-lives and potentially to toxicity problems. Accordingly,
the only receptors to which covalent binding is desirable are those that belong to exoge-
nous (or “non-self”) targets, including viruses, bacteria, parasites, or tumours (see sec-
tions 9.1 and 9.2). In short, it is okay for a drug to covalently bind to a disease-causing
bacterium, but it is not okay for a drug to covalently bind to a diseased liver.

70 MEDICINAL CHEMISTRY

Table 2.1Chemical Bonds and Average Bond Energies

Total interaction Electrostatic Charge-transfer
energy, energy, energy,
−∆E −∆Ees ∆Eet
Bond type Example (kJ/mol) (kJ/mol) (kJ/mol)

Dispersion Xe...Xe 1.9 0 0
(van der Waals)
Hydrophobic C 6 H 6 ...C 6 H 6 4.2 ≠ 0 ≠ 0
Hydrogen H 2 O...H 2 O37 38 9

Charge transfer 17 16 4

Dipole–dipole ~5

Ion–dipole F
...H 2 O 171 154 75
Ionic NH 4 ⊕F
685 757 149
H⊕Cl
450

Covalent 346

614

(Modified from Stenlake (1979) and Kollman (1980).)

C

C

NC CN

NC CN

H 2 O

CO

NR 3

CC

CC