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 measurements, 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 provide 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 molecular structure with biological activity during the drug molecular 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-Gyrgyi (1960), in his brilliant pioneering book onsubmolecular biology, directed attention to charge-transfer complexes (see section 2.3.5). The energies of the highest occupied molecular orbital (HOMO) and the lowest unoccupied 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 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 reactive regions on the molecule undergo metabolism to form reactive 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.