Medicinal Chemistry

1.6.3 Applications of Quantum Pharmacology Calculations

to “Small Molecule” Drug Studies

Most drug molecules are classed as “small molecules”, that is, molecules with a mole-
cular weight less than 800. Such molecules are ideally suited to having their structures
probed and understood using quantum pharmacology calculations (see figure 1.14). More

52 MEDICINAL CHEMISTRY

Mechanics

methods

• Molecular mechanics


• Quantum mechanics

Conformational

search

algorithms

• Molecular dynamics


• Monte Carlo

Energy

minimization

algorithms

• Steepest descent


• Newton-Raphson

Multiple

minima

Global minimum

Molecular conformation

A

B

Energy Local minimum

Figure 1.13 Mechanics methods assign an energy value to all possible shapes and geometries
of a drug molecule or receptor macromolecule. The set of all possible shapes of a molecule
defines the potential energy hypersurface for that molecule, shown in two dimensions in Part B.
When attempting to identify the most probable shape of a molecule, it is necessary to search the
hypersurface for the lowest energy shape (global minimum). Because of the many millions of
valleys on such a surface (multiple minima), it is difficult to find the true global minimum and
not just one particular local minimum. Conformational search algorithms permit an approach to
“hopping” across the hypersurface in an attempt to sample it and, hopefully, find the region of
the global minimum. Once the region of a minimum has been identified, energy minimization
algorithms permit the bottom of the minimum energy well to be attained.