mechanics, appeared able to rigorously represent the physical properties of reality,
including natural objects as large as planets or as small as billiard balls. However,
through the work of Bohr and others, it was eventually realized that classical Newtonian
mechanics failed at the atomic level of reality—atoms did not behave like billiard balls.
An alternative approach was needed for the quantitative evaluation of molecular phe-
nomena. Molecular quantum mechanics was to be such an approach.
In the first three decades of the 20th century, there occurred many significant
advances in theoretical physics and physical philosophy. Planck showed that energy is
emitted in the form of discrete particles or quanta; Einstein expanded upon this theory
with the proposal that an atom emits radiant energy only in quanta, and that this energy
is related to the mass and to the velocity of the light; Schrödinger incorporated these
evolving ideas of the new quantum theory into an equation that described the wave
behavior of a particle (wave mechanics); Heisenberg formulated a complete, self-
consistent theory of quantum physics, known as matrix mechanics; and Dirac showed
that Schrödinger’s wave mechanics and Heisenberg’s matrix mechanics were special
cases of a larger operator theory. The capacity for a robust, mathematical description of
molecular-level phenomena seemed to be at hand.
Since the Schrödinger equation (which lies at the mathematical heart of quantum
mechanics) permitted quantitative agreement with experiment at the atomic level, the
physicists of the 1930s predicted an end to the experimental sciences, including biology,
suggesting that they would merely become a branch of applied physics and mathematics.
These hopes were excessively optimistic and soon proved groundless. Although in princi-
ple the Schrödinger equation afforded a complete description of Nature, in practice it could
not be solved for the large molecules of medical and pharmacological interest. Early hopes
that quantum mechanics would solve the problems of drug design were dashed in despair.
Over the past thirty years, however, three advances have changed the practical use-
fulness of molecular quantum mechanics:
- The advent of semi-empirical molecular orbital calculations and density functional
theory, which employ mathematical assumptions to simplify the application of
quantum mechanics to drug molecules of intermediate to large size. - The development of molecular mechanics, which incorporates quantum mechanical
data into a simplified mathematical framework derived from the classical equations
of motion to permit reasonable calculations on biomolecules of large size. - The construction of “supercomputers” capable of performing the massive calcula-
tions necessary for considering very large biomolecules. Accordingly, quantum
pharmacology has become an attainable goal and calculational computer modeling
permits large molecules to be studied meaningfully.
Computer-assisted molecular design (CAMD) employs these powerful computational
techniques to engineer molecules for desired receptor site geometries. CAMD had gained
widespread acceptance and is beginning to prove its usefulness in many realms of phar-
macological endeavor. It has the potential to profoundly influence the future of rational
drug design. CAMD enables rigorous modeling of drug molecules, of receptor macro-
molecules, and of complex drug–receptor interactions. All of these calculations are
immensely important to rational drug design.
120 MEDICINAL CHEMISTRY