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substituent is most likely pointed out of the active site
into the solvent.
In conclusion, we have established a new ZBG for inhi-
bition of MMPs. Compounds with only a minimal num-
ber binding groups (potential zinc and S10 binding)
demonstrated low micromolar activity against MMP-9.
These compounds were also selective for inhibition of
gelatinase B over other MMPs. The SAR data is consist-
ent with the supposition that the oxazoline 2-substituent
is positioning itself in the S10 pocket of the enzyme as
these substituents would not be expected to bind well
into the S10 pocket of MMP-1 owing to its shallow
depth. The oxazoline 5-substituent appears not to che-
late with the zinc and the size and electronic nature of
this substituent could be varied without significant
change in activity.
2. (a) Sternlicht, M. D.; Lochter, A.; Sympson, C. J.; Huey,
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3. For an excellent example of a simple sulfonamide carb-
oxylate bound to the zinc and S10 pocket, see: Pavlovsky,
A. G.; Williams, M. G.; Ye, Q.-Z.; Ortwine, D. F.;
Purchase, C. F., II; White, A. D.; Dhanaraj, V.; Roth, B.
D.; Johnson, L. L.; Hupe, D.; Humblet, C.; Blundell, T. L.
Protein Sci. 1999, 8, 1455.
4. For recent studies of other potential MMPI ZBGÕs with
model zinc complexes, see: (a) Puerta, D. T.; Lewis, J. A.;
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Acknowledgements
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We are grateful to the National Institutes of Health
(NCRR-P20-RR15566) for support of this work. The
molecular graphics image in Figure 1a was produced
using the UCSF Chimera package from the Computer
Graphics Laboratory, University of California, San
Francisco (supported by NIH P41 RR-01081).
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MMPs. For a discussion of the similarity of MMP binding
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