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Document<br />

VII. Conclusions<br />

Page 243<br />

The observation of a protein undergoing a conformational change when binding to an inhibitor, as seen<br />

with ALR2 and zopolrestat, illustrates a common problem associated with structure-<strong>based</strong> drug design.<br />

It is tempting to view proteins as static structures since their crystal structures are static. Attempts to<br />

design drugs to fit the apparent active site of an enzyme may fail when the plasticity of the protein is not<br />

taken into account. While the disorder associated with amino acid side chains can be modeled with a<br />

moderate computational effort, larger conformational changes—such as the loop movement seen in<br />

ALR2—are virtually impossible to predict. Until this becomes possible, x-ray crystal structures of<br />

complexes will continue to be indispensible.<br />

Finally, it can be easy to forget that a compound's affinity for the protein is not the only consideration<br />

when designing inhibitors of enzymes from a structural point of view. The structures of aldose reductase<br />

and the FR-1 protein complexed with the drug zopolrestat, a compound with a very high affinity for<br />

ALR2, can serve as a reminder of how specificity can also be a very important factor. This is<br />

particularly true when a protein is a member of a family of proteins that share sequence homology and<br />

are apt to have overlapping specificities. <strong>Structure</strong> may then play a key role in the determination of<br />

features that are unique to the target protein and therefore prime considerations when designing<br />

inhibitors.<br />

Acknowledgments<br />

We thank T. Reynolds who assisted with the production of the figures. This work was supported <strong>by</strong> a<br />

grant from Research to Prevent Blindness, Inc. and grants EY05856, EY02687, and DK20579 to J. Mark<br />

Petrash. Florante A. Quiocho is an investigator of the Howard Hughes Medical Institute.<br />

References<br />

1. Kinoshita JH, Nishimura C. The involvement of aldose reductase in diabetic complications. Diabetes-<br />

Metebolism Rev 1988; 4:323–337.<br />

http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_243.html (1 of 2) [4/5/2004 5:09:27 PM]

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