netLibrary - eBook Summary Structure-based Drug Design by ...

Document
Figure 4
Surface representation of the ALR2 holoenzyme in an orientation similar to Figure 3.
The nicotinamide moiety that defines the active site of the enzyme is seen in the center.
The groove that extends down from it is highly hydrophobic and was initially assumed
to be the inhibitor binding site. Figure prepared using the GRASP program [49].
IV. Aldose Reductase Complexed with Inhibitor
Page 235
While a large number of high-potency inhibitors for ALR2 have been developed [4], a structural
understanding of the exact molecular features that foster this affinity have been only vaguely
understood. Several general chemical motifs such as hydrophobic ring systems, a spirohydrantoin group
or carboxylate group are seen repeatedly when examining a list of known inhibitors (Figure 2) but little
was known about the specific role for each in inhibitor binding.
The structure of the ALR2/NADPH/zopolrestat ternary complex [18] has provided some answers about
the mode of binding of zopolrestat (Figure 2), a high-affinity, carboxylate-containing compound
developed by Pfizer, Inc. [13]. While the overall structure was preserved, the inhibitor binding induced a
conformational change of the enzyme. This change, which involved the movement of several loops in
the active site of the molecule, was large enough to cause a change in crystal packing relative to the
holoenzyme. As a consequence of the shifting of the active-site loops, a cavity is created inside the
protein in which the benzothiazole ring is seated and the groove that was implicated in substrate and
inhibitor binding by the holoenzyme structure vanishes. This illustrates the unpredictability of
conformational changes within a protein in response to substrate or inhibitor binding. It also implies that
modeling compounds
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_235.html [4/5/2004 5:08:24 PM]