Chemistry Reference
In-Depth Information
Table 16 Influence of the environment on atomic charges (Roby-Davidson scheme) [
123
,
124
]of
AMCHA
Center or group
g/g
s/s
p/p
p/g
p/s
c/c
O1
0.43
0.44
0.52
0.32
0.46
0.53
O2
0.56
0.50
0.50
0.40
0.49
0.46
0.02
0.01
0.02
0.03
C1
0.43
0.03
0.56
0.96
1.02
0.74
0.98
0.95
Carboxylate
N1
0.13
0.18
0.06
0.11
0.15
0.04
H1
0.13
0.16
0.22
0.15
0.16
0.22
H2
0.16
0.15
0.15
0.14
0.16
0.20
H3
0.14
0.15
0.22
0.14
0.17
0.19
Ammonium
0.56
0.64
0.66
0.54
0.64
0.66
Cyclohexane ring
0.11 0.23 0.23 0.14 0.20 0.22
All values are given in (a.u.). The numbering of the centers can be taken from Fig.
1
; further
abbreviations from Table
8
K
i
k
i
Scheme 1 Two-step model
for irreversible inhibition of
enzymes.
E
enzyme,
EI
reversible, noncovalent
enzyme-inhibitor complex,
E-I
irreversible, covalent
enzyme-inhibitor complex
E + I
EI
E-I
been optimized for the reaction with the substrate in the evolutionary process which
is not the case for irreversible inhibitors. Their inhibition potency may result from
their inherent chemical reactivity and less from the influence of the enzyme. In this
case, the influence of the enzyme environment on the EDs could be as small as for
reversible inhibitors. As first test examples, we chose E64-derived compounds
(Fig.
5
). They are irreversible inhibitors of cysteine proteases, which represent
promising drug targets for osteoporosis [
125
], arthritis [
104
], cancer [
126
], and
Alzheimer's disease [
125
]. They react in a two-step mechanism (Scheme
1
)[
127
,
128
]. In the first step, a reversible noncovalent enzyme-inhibitor complex EI is
formed. The stability of this complex arises from reversible interactions between
ligand and enzyme. The second step is initiated by the nucleophilic attack of the
negatively charged Cys thiolate at C
a
of the epoxide moiety. Subsequently, a ring
opening reaction happens in which a new S-C
a
bond is formed while the C
a
-O
bond of the epoxide is broken.
The investigations for the E64c compounds started from the crystal structure of
the covalently bonded cathepsin B-E64c complex (1ITO) [
129
], which is the final
product of the two-step mechanism (Scheme
1
). The preparation of the system was
performed as described for AMCHA. The resulting structure is shown in Fig.
11
.
The molecular structure of the environment is indicated by sticks, while E64c is
shown in ball and stick representation. The numbering of the centers of E64c is also
given. The main interactions between E64c and the active site of cathepsin B are
indicated by arrows.
