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 βunits (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 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.
1.6 PREDICTING THE PROPERTIES OF DRUG
MOLECULES: QUANTUM MECHANICS
AND MOLECULAR MECHANICS
When confronted with the task of designing drugs, it would be wonderful to have a
method for predicting the properties of drug molecules before having to actually syn-
thesize and purify them. The synthetic preparation of new molecules is challenging,
time consuming, and expensive. Theoretical chemistry, combined with modern compu-
tational methods, offers a powerful solution to this prediction dilemma.
The docking of a drug with its receptor site is a precise interaction between two mole-
cules. The success of this interaction is dependent upon the geometry, conformation and
electronic properties of the two molecules. Designing drugs requires techniques for deter-
mining and predicting the geometry, conformation, and electronic properties of both small
molecules (i.e., drugs with molecular weights less than 800) and macromolecules (i.e.,
receptor proteins.) Quantum pharmacology and molecular modeling calculations are such
techniques. Molecular modeling is the evaluation of molecular properties and structures
using computational chemistry and molecular graphics to provide three-dimensional visu-
alization and representation of molecules. Quantum pharmacology is the application of
the methods of modern computational chemistry to understanding drug action at the
molecular and atomic level of structural refinement. CADD (computer-aided drug design)
and CAMD (computer-aided molecular design) are the employment of computer-aided
techniques to design, discover, and optimize bioactive molecules as putative drugs.
DRUG MOLECULES: STRUCTURE AND PROPERTIES 43