Chemistry Reference
In-Depth Information
Using more sophisticated models (replacing the missing water molecules by
COSMO or point charges) yields almost identical values. Hence, we refrain from
further discussions which would give no additional insights.
5 Summary and Conclusions
This chapter reviews works that examined how different environments affect EDs
and related properties. The first part summarized investigations on the reliability
of pure theoretical approaches which showed that while absolute numbers for
electron densities and Laplacian values are not easily obtained by such theoretical
methods, they are suitable for a reasonable reproduction of the trends related to
the properties of EDs. The second part considers whether properties of the ED
can be used to understand the inhibition potency of possible drugs. The examples
of AMCHA, a reversible inhibitor, and of E64c or E64d, as prototypes for
irreversible inhibitors, were discussed in detail. AMCHA binds to the target
enzyme via intermolecular interactions such as hydrogen bonds, salt bridges, or
hydrophobic effects, whereas the latter inhibitors form strong covalent bonds to
their target enzyme. In both cases, EDs and properties were computed in four
different environments: gas phase, polar solvent, crystal, and inhibitor-enzyme
complex. Polar solvents were mimicked by the COSMO method which accounts
for the polarizability of the surrounding medium. For crystal and protein sur-
rounding, the atomistic nature of the environment was explicitly represented by a
QM/MM approach. To distinguish between direct environmental influences and
variations which result more indirectly from different geometries, various model
systems were investigated.
In all cases, the influence of the environment on the ED increases in the order
gas phase
protein. This shows again that proteins
can polarize molecules stronger than environments inside of crystals of the pure
compound. For the reversible inhibitor, AMCHA, the deviations due to different
environments are reflected in the computed data, but they are smaller than the
uncertainties of high resolution X-ray experiments (0.1 e/
˚
3
for EDs, 4-5 e/
˚
5
for Laplacians). This supports the assumption that for such inhibitors the ED
taken from high-resolution X-ray measurements of crystals of the pure compound
can be transferred to related enzyme-inhibitor complexes. It also explains why
data taken from the Cambridge structure database are useful for scoring functions
used in docking procedures. The differences found for the irreversible inhibitor
E64c are much stronger. Hence, the very strong intermolecular bonding interac-
tions between the carboxylate and the enzyme-environment pull the inhibitor
onto the thiolate. As a result, the C
a
-O bond of the epoxide is considerably
weakened and the reactant structure is strongly distorted. The resulting change in
the ED is so strong that it cannot be foreseen by measurements or computations
in other surroundings. Hence, prediction of the reactivity of irreversible inhibitors
<
polar solvent
<
crystal
<
