Biomedical Engineering Reference
In-Depth Information
+
O
O
N
O
N
NH
NH
N
δ+
NH
OH
OH
N
OH
N
N
δ+
N
O
O
O
N
1.77Å
N
O
1.44Å
OH
3.0Å
O
-
P
OH
O
-
HO
HO
OH
O
O
-
OH
OH
O
P
OH
P
O
OH
O
-
O
-
O
N
NH
OH
NH
+
N
OH
HO
Immucillin H
FIGURE 11.6
The structures of PNP reaction substrate inosine, transition state, and reaction product (top
panel) and transition state-based inhibitor Immucillin H (bottom panel).
Immucillin H was a 56 pM inhibitor of human PNP with good potency against cultured human
T-cell lines in the presence of deoxyguanosine. Currently, Immucillin H is in phase II clinical trials
for the treatment of leukemia.
11.5 BIOSTRUCTURE-BASED DESIGN
In the preceding section of this chapter we established the fundamental importance to drug discov-
ery of a deep, mechanistic understanding of the reaction mechanism of an enzyme target. While
this can be accomplished by the application of mechanistic enzymology, it can be facilitated greatly
by the knowledge of the three-dimensional structure of the protein, obtained via biostructure-based
technologies such as computational biochemistry, NMR spectroscopy, and x-ray crystallography.
Visualization of the detailed architecture of an enzyme's active site, in complex with a small-molecule
inhibitor, can be an important driver in the optimization of a medicinal chemistry effort. The struc-
tural insights thus obtained allow for improvements in target potency, selectivity, and inhibitor
physicochemical properties, all of which are paramount in establishing inhibitor SAR.
The term “rational drug design” is often used to describe the application of structure-guided
drug discovery approaches. Over the past two decades, several drugs have been made available
to patients as a result of advances in protein crystallography and other structural methods. For
example, more than 40 compounds have entered clinical trials whose discovery was reliant upon
a biostructure-based approach, and as of 2007, at least 10 of these have been approved by regula-
tory agencies. In this section, we exemplify how a detailed understanding of the topography of a
ligand-enzyme complex can provide a basis for the design of better inhibitors and can complement
enzymological studies to rationalize their biochemical mode of action.
