Biomedical Engineering Reference
In-Depth Information
enzyme for substrate) and also decrease the apparent value of
k
cat
(i.e., diminishing the ability of the
enzyme to catalyze chemical steps subsequent to substrate binding). Among drugs in current clini-
cal use one i nds multiple examples of each of these three modalities of enzyme inhibition.
11. 3 PROTEIN DYNAMICS IN ENZYME CATALYSIS
AND INHIBITOR INTERACTIONS
The catalytic pathway summarized in Equation 11.1 is a gross oversimplii cation of even the sim-
plest of enzymatic reactions. At minimum, this reaction requires the formation of two additional
forms of enzyme-ligand binary complex, these being the enzyme-transition state complex and
the enzyme-product complex. In practice, one often i nds that additional intermediate states are
accessed during the catalytic cycle of an enzyme. Thus, one can say that the catalytic cycle of an
enzyme is a sequential series of protein-ligand complexes, each representing a unique chemical
form of the ligand with attendant changes in the protein conformation of the ligand-binding pocket.
Each conformational state of the ligand-binding pocket that is accessed during this catalytic cycle is
a potential target for small molecule drug interactions. Hence, one can think of the ligand-binding
pocket of an enzyme not as a single target for drug intervention, but rather a collection of targets
that evolve and interconvert over the time course of catalytic turnover.
To illustrate these concepts, let us consider the reaction cycle of an aspartyl protease. The aspartyl
proteases constitute a family of protein/peptide hydrolyzing enzymes that use a pair of aspartic
acid residues within the enzyme active site to facilitate peptide bond cleavage. Figure 11.1 provides
O
H
H
H
P
1
'
N
H
2
O
O
O
P
1
O
H
O
O
O
H
E
H
HO
O
O
O
O
H
O
O
O
G
ES
Flap closing
H
N
P
1
'
P
1
HO
O
O
O
H
O
O
H
H
HO
O
O
O
F
E'S
H
H
N
P
1
'
O
H
P
1
H
P
1
N
P
1
'
O
H
O
P
1
N
O
O
P
1
'
H
H
H
O
O
O
H
OH
O
O
O
OH
HO
O
O
OH
HO
E'S
‡
FP
E'P
FIGURE 11.1
The reaction pathway for an aspartyl protease. (Adapted and modii ed from Copeland, R.A.,
Evaluation of Enzyme Inhibitors in Drug Discovery
:
A Guide for Medicinal Chemists and Pharmacologists
,
Wiley, Hoboken, NJ, 2005.)
