The correct geometry, conformation, and stereochemistry of a molecule permit it to gain access to the receptor microenvironment. However, it is the electronic structure of the molecule that enables the electrostatic, hydrogen bonding, and other drug–receptor binding interactions to actually occur. The chemical structure of a drug molecule, its chemical reactivity, and its ability to interact with receptors ultimately depend on its electronic structure—the arrangement, nature, and interaction of electrons in the mole-cule. In general, the effect of electron distribution in organic compounds can be direct (short range) or indirect (long range).
Direct electronic effects primarily concern covalent bonding, which involves the overlap of electron orbitals. The “strength” of covalent bonds, the interatomic distances spanned by these bonds, and dissociation constants are all direct consequences of the nature of covalent electrons. The nonbonding electron pairs of such heteroatoms as O, N, S, and P also play an important role in drug characteristics. They are the basis of such noncovalent interactions as hydrogen bonding (which, as already discussed, has a profound effect on the hydrophilic or lipophilic characteristics of a molecule), charge-transfer complex formation, and ionic bond formation. In all of these phenomena, the nonbonding electron pair participates in a donor–acceptor interaction.
Indirect electronic effects occur over a longer range than direct effects, requiring no orbital overlap. Electrostatic ionic interactions fall partly within this category, since the
(1.12)
(1.13)
effect of inter-ionic forces decreases by the square of the distance over which they act.
Such inductive forces as van der Waals bonds and dipole moments are the results of polarization or polarizability—the permanent or induced distortion of the electron dis-tribution within a molecule. These forces are especially important in studies of quanti-tative structure–activity relationships (QSAR) because the electronic effect of a substituent can, by resonance or an inductive or field effect, change the stereoelectronic properties of a molecule and thus influence its biological activity.
1.5.1 Quantifying Drug Molecule Electronic Properties:
The Hammet Correlations
There have been many attempts to quantify the electronic properties of drug molecules.
Hammet correlations were among the first to be used and represent the classical way of quantifying electronic properties. The Hammet correlations (Hammet, 1970) express quantitatively the relationship between chemical reactivity and the electron-donating or electron-accepting nature of a substituent. Historically, they have been perhaps the most widely used electronic indices in QSAR studies of drugs. The Hammet substituent constant (σ) was originally defined for the purpose of quantifying the effect of a substituent on the dissociation constant of benzoic acid:
where KXis the dissociation constant of benzoic acid carrying substituent X; KHis the dissociation constant of unsubstituted benzoic acid. Electron-attracting substituents have a positive σvalue, while electron-donating substituents (—OH, —OCH3, —NH2, —CH3) have a negative σ. The value of σalso varies according to whether the substituent is in the meta or para position. Ortho substituents are subject to too many interferences and are not used in calculating σ. Detailed tables of σvalues can be found in the works of Chu (1980) and Albert (1985).
The Hammet substituent constant includes both inductive and resonance effects (i.e., electronic influences mediated through space and through conjugated bonds). In the case of benzoic acids, direct conjugation is not possible, but in one resonance hybrid, as shown in figure 1.14, the electron-withdrawing nitro group puts a positive charge on the C-1 carbon, thus stabilizing the carboxylate ion and decreasing the pKaof the sub-stituted acid. The electron-donating phenolic hydroxyl group, on the other hand, desta-bilizes the carboxylate anion by charge repulsion, making the substituted acid weaker.
1.5.2 Ionization of Drug Molecules
Ionization is another crucial property of the electronic structure of a drug molecule. The pKaof a drug is important to its pharmacological activity since it influences both the absorption and the passage of the drug through cell membranes. In some cases, only the ionic form of a drug is active under biological conditions.
Drug transport during the pharmacokinetic phase represents a compromise between the increased solubility of the ionized form of a drug and the increased ability of the non-ionized form to penetrate the lipid bilayer of cell membranes. A drug must cross many lipid barriers as it travels to the receptor that is its site of action. Yet cell membranes
log KX/KH = σ (1.5)
contain many ionic species (phospholipids, proteins) that can repel or bind ionic drugs; and ion channels, usually lined with polar functional groups, can act in an analogous manner.
Ionic drugs are also more hydrated; they may therefore be “bulkier” than nonionic drugs.
As a rule of thumb, drugs pass through membranes in an undissociated form, but act as ions (if ionization is a possibility). A pKain the range of 6–8 would therefore seem to be most advantageous, because the nonionized species that passes through lipid membranes has a good probability of becoming ionized and active within this pKarange. This consid-eration does not relate to compounds that are actively transported through such membranes.
A high degree of ionization can prevent drugs from being absorbed from the gastroin-testinal tract and thus decrease their systemic toxicity. This is an advantage in the case of externally applied disinfectants or antibacterial sulfanilamides, which are meant to remain in the intestinal tract to fight infection. Also, some antibacterial aminoacridine derivatives are active only when fully ionized. These now obsolete bacteriostatic agents intercalate (position or interweave themselves) between the base pairs of DNA. The cations of these drugs, obtained by protonation of the amino groups, then form salts with the DNA phos-phate ions, anchoring the drugs firmly in position. Ionization can also play a role in the electrostatic interaction between ionic drugs and the ionized protein side chains of drug receptors. Therefore, when conducting experiments on drug–receptor binding, it is advis-able to regulate protein dissociation by using a buffer. The degree of ionization of any compound can be easily calculated from the Henderson–Hasselbach equation:
1.5.3 Electron Distribution in Drug Molecules
More recently, a variety of other methods has been developed to describe the electronic distribution properties of drug molecules. The electron distribution in a molecule can be estimated or determined by experimental methods such as dipole-moment measure-ments, NMR methods, or X-ray diffraction. The latter method provides very accurate electron-density maps, but only of molecules in the solid state; it cannot be used to pro-vide maps of the nonequilibrium conformers of a molecule in a physiological solution.
To provide easily obtained yet rigorous assessments of electron distribution properties, quantum mechanics calculations are now employed (see section 1.6). Molecular quantum mechanics calculations provide several methods for calculating the orbital energies of atoms, combining the individual atomic orbitals into molecular orbitals, and deriving from the latter the probability of finding an electron at any atom in the molecule—
which is tantamount to determining the electron density at any atom. There are several methods for doing this, with varying degrees of sophistication, accuracy, and reliability.
These calculations permit quantification of the charge density on any atom in a drug molecule. Such atomic electron density values may be used when correlating molecu-lar structure with biological activity during the drug molecumolecu-lar optimization process.
In addition to providing values for charge densities on individual atoms, quantum mechanics calculations may also be used to determine the energies of delocalized orbitals; such energy values may also be used when correlating molecular structure with pharmacologic activity. The energies of delocalized orbitals have attracted considerable interest since the early 1960s, when Szent-Györgyi (1960), in his brilliant pioneering book
% ionized= 100/(1 + antilog [pH − pKa]) (1.6)
on submolecular biology, directed attention to charge-transfer complexes (see section 2.3.5).
The energies of the highest occupied molecular orbital (HOMO) and the lowest unoccu-pied molecular orbital (LUMO) are a measure of electron-donor and electron-acceptor capacity, respectively, and consequently determine donors and acceptors in charge-transfer reactions. HOMO and LUMO are also reliable estimates of the reducing or oxidizing properties of a molecule. They are expressed in β units (a quantum-chemical energy parameter whose value varies from 150 to 300 U/mol). The smaller the numerical value of HOMO (a positive number), the better the molecule is as an electron donor, since the small number indicates that less energy is required to remove an electron from it.
Likewise, the smaller the magnitude of the LUMO (a negative number), the more stable the orbital for the incoming electron, which favors electron-acceptor characteristics.
Thus, by examining the numerical values of the HOMO and LUMO of a pair of drug molecules, one can often decide whether a charge-transfer complex can be formed, and which compound will be the donor and which the acceptor.
In addition to providing insights concerning correlation of molecular structure with pharmacologic bioactivity, quantum mechanics calculations of electron distribution may also be employed to understand the molecular basis of drug toxicity. For instance, overall p-electron density of polycyclic hydrocarbons has traditionally been assumed to correlate with the carcinogenicity of these compounds. According to this hypothesis, defined reac-tive regions on the molecule undergo metabolism to form reacreac-tive intermediates such as epoxides, which react with cell constituents such as the basic nitrogen atoms in nucleic acids. Although this model has been widely cited in the literature, it is appropriate to warn the reader that, however attractive, it is seriously questioned. However, p-electron density is very important in the chemical reactivity of aromatic rings.
1.6 PREDICTING THE PROPERTIES OF DRUG