Chemistry Reference
In-Depth Information
datasets are only available for a single protein-ligand complex: the human aldose
reductase with the inhibitor IDD594 [
65
-
67
].
For the reasons described above, EDs of inhibitors in enzyme-inhibitor complexes
can in general only be
approximated
by EDs obtained from crystals of the pure
inhibitor compound [
17
-
19
,
40
,
68
-
72
]. Although the stability of crystals of pure
compounds and enzyme-inhibitor complexes is governed by the same types of
intermolecular interactions (e.g., steric, electrostatic, hydrogen bonding, van der
Waals effects), it is by no means obvious that a crystalline environment is a good
approximation for that of an enzyme [
73
]. Support for this assumption comes from the
finding that in enzyme-inhibitor complexes as well as in crystals of the pure com-
pound, the interacting species often arrange in a way that bonding interactions are
optimized. Evidence, that the spatial orientations in crystals of small organic mole-
cules are indeed representative for arrangements of inhibitors in enzymes, is given in
studies which analyze the Cambridge structural data bank (CSD) to elucidate pre-
ferred orientations of functional groups with respect to each other [
74
]. These orienta-
tions were indeed shown to be in qualitative agreement with arrangements in
protein-inhibitor complexes from the RCSB protein data bank (PDB) [
64
,
75
-
77
].
Nevertheless, due to the enormous catalytic power of enzymes, one would expect that
the enzyme environment will influence the ED of the inhibitor in a unique fashion.
Investigations comparing EDs obtained from crystals of the pure compound and from
enzyme-inhibitor complexes are not available. Such investigations may demonstrate
to which extent EDs of pure inhibitor crystals can be used to quantify the molecular
recognition process between an enzyme and an inhibitor. Insights into the expected
differences are also of interest for new approaches which use predetermined atomic
EDs to build up EDs of macromolecules, e.g., proteins [
45
,
78
-
80
]. The quality of the
composed EDs might be substantially improved by including the expected influence
of the environment in the predetermined EDs [
81
,
82
].
In the present review, we will report on recent results about the influence of
environments on the ED of inhibitors [
83
]. In these works, the EDs of agents in gas
phase, polar solvents, crystals, and enzyme environments were compared. These
are theoretical studies, since pure experimental approaches are yet not feasible and
a mixing of experimental and theoretical values is cumbersome and ambiguous.
The quality of the theoretical approach required to achieve this goal is discussed in
the first part of this review. As example, we use a series of sulfur-nitrogen bonds
possessing a varying degree of polarity. The studies used various theoretical
approaches to investigate the convergence of the ED and its topological properties
with respect to basis set size and theoretical methods. Furthermore, they focused on
the prediction of trends since this is sufficient for correct judgments of the environ-
mental influences.
Similar EDs do not necessarily result from similar environmental influences.
They may also be caused by a compensation of different effects. This can be
investigated using the source function [
44
,
84
] which provides the contribution of
different atomic basins on the ED at any given point in space. Hence, in the last part
of the review we will report on the applicability of the source function for theoreti-
cal approaches that are frequently used to investigate enzyme-inhibitor complexes.
