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 difficulties 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 exogenous (or “non-self”) targets, including viruses, bacteria, parasites, or tumours (see sections 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.
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MEDICINAL CHEMISTRY
Table 2.1 Chemical Bonds and Average Bond Energies
Total interaction
Electrostatic
Charge-transfer
energy,
energy,
energy,
−∆E
−∆E es
∆E et
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 O
3 7
3 8
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
C
O
NR 3
C
C
C
C
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 difficulties 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 exogenous (or “non-self”) targets, including viruses, bacteria, parasites, or tumours (see sections 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 2.1 Chemical Bonds and Average Bond Energies
Total interaction
Electrostatic
Charge-transfer
energy,
energy,
energy,
−∆E
−∆E es
∆E et
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 O
3 7
3 8
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
C
O
NR 3
C
C
C
C