A second application of quantum pharmacology is in the process of pseudoreceptor
mapping. If, the pharmacophore for a family of drug molecules has been determined
by means of QSAR calculations, then it is possible to deduce what the corresponding
receptor should look like. For instance, if the pharmacophore has a positively charged
ammonium located 6 Å from a hydrogen bonding acceptor, then the corresponding
receptor site may have a negatively charged carboxylate and a hydrogen bonding donor
located in an appropriate geometric orientation. Establishing the geometry of the model
receptor (or pseudoreceptor map) can be achieved using either quantum mechanics or
molecular mechanics calculations. Therefore, even though the structure of the actual
receptor is unknown, the nature of the molecular properties that it should have can be
ascertained. In principle, this pseudoreceptor map can be used to design or identify
other molecules capable of docking with it.
A third important application of quantum pharmacology/molecular modeling is its
use in de novodrug design of novel molecular shapes that will fit into a known recep-
tor site. If the molecular structure of a receptor protein has been solved by experimen-
tal methods such as X-ray crystallography, and if the location of a potential receptor site
within this protein has been deduced, then it may be possible to design small molecules
to fit into this receptor site. By identifying hydrogen bonding donors or acceptors and
other points for intermolecular interactions on the receptor site, it is possible to design
complementary molecules to fit into this site. In short, this is the process of designing
a pharmacophore and then designing the molecular baggage around the pharmacophore
to ensure that the functional groups are held in an appropriate three-dimensional
arrangement. Molecular mechanics and quantum mechanics are well suited to this task
of designing new molecules as putative drugs.
1.6.4 Applications of Quantum Pharmacology to Large Molecule StudiesAlthough quantum pharmacology calculations are more rigorous and robust when
applied to small molecules, such calculations may also be applied to macromolecules.
There are few drug molecules that are macromolecules; peptides, such as insulin, are
the exception. Usually, it is the receptor that is the macromolecule. Although receptors
are discussed in detail in chapter 2, the role of quantum pharmacology in optimizing the
structure of macromolecules will be presented here.
The most important potential application of quantum pharmacology to macromolec-
ular modelling is in the area of protein structure prediction. Protein structure may be
considered at multiple levels of refinement: primary structure refers to the amino acid
sequence; secondary structure is defined by the local conformations induced by hydro-
gen bonding along the peptide backbone (e.g.,α-helix,β-sheet,β-turn); tertiary struc-
ture concerns the three-dimensional structure of the protein arising from hydrogen
bonding, electrostatic interactions, and other intramolecular interactions involving
either side-chain or backbone functional groups; quaternary structure refers to the
three-dimensional structure of proteins composed of more than one peptide chain. From
this hierarchical system of structure arises the fundamental question (called the protein
folding problem) in applying computational chemistry to protein structure: does
the primary amino acid sequence determine the three-dimensional structure of a pro-
tein, and, if so, what are the rules that will permit us to predict tertiary structure with
54 MEDICINAL CHEMISTRY