Curr Pharm Des. 2005;11(3):295-322.
Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies.
Rao BG1.
Abstract
It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP)
was revealed for the first time in 1994. More than 80 structures of
different MMPs in apo and inhibited forms, determined by X-ray
crystallography and NMR methods, have been published by the end of year
2003. A large number of very potent inhibitors have been disclosed in
published and patent literature. Several MMP
inhibitors entered clinical trials for the treatment of cancer and
arthritis. Most of the first generation inhibitors have hydroxamic acid
as the Zinc-binding group and have limited specificity. With the failure
of these inhibitors in clinical trials, more efforts have been directed
to the design of specific inhibitors with different Zn-binding
groups in recent years. This review will summarize all the published
structural information and focus on the inhibitors that were designed to
take advantage of the nonprime side of the MMP
active site using structural information and computational analysis.
Representative structures from all MMPs are aligned to a target
structure to provide a better understanding of the similarities and
differences of the active site pockets. This analysis supports the view
that the differences in the nonprime side pockets provide better
opportunities for designing inhibitors with higher specificity.
Published information on all the Zinc-binding groups of MMP
inhibitors is reviewed for the first time. Pros and cons of inhibitors
with non-hydroxamate Zinc-binding groups in terms of specificity,
toxicity and pharmacokinetic properties are discussed.
- PMID:
- 15723627
- DOI:
- 10.2174/1381612053382115
- [Indexed for MEDLINE]
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