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VOL. 73 (3), 703-746, 2007 ARE ADRENOMEDULLIN POSITIVE MODULATORS NOVEL...

Matrix Metalloproteinases Inhibitors (MMPIs)

Many groups of compounds are used as MMPs inhibitors. The
requirements for a molecule to be an effective MMP inhibitor are:
a) a functional group (e.g. carboxylic acid, hydroxamic acid,
sulfhydryl, etc.) capable of chelating the catalytic Zn2+ ion (this will be
referred as zinc binding group or ZBG); b) at least one functional
group which provides a hydrogen bond interaction with the enzyme
backbone; and c) one or more side chains that undergo effective van
der Waals interactions with the enzyme subsites. These requirements
can be satisfied by a variety of different structural classes of MMP
inhibitors, which have been discovered by a number of methods,
including structure-based design (5) and combinatorial chemistry (7).

Zn2+-chelating hydroxamates have been the most frequently used
ZBG in MMPI design, because of their higher ?G values, but as
shown below, a number of other groups are possible. However,
strong Zn2+-chelating moieties disproportionately drive binding mode
and make the contributions from the rest of the compound smaller,
reducing other opportunities for improved specificity. Indeed, it
has been demonstrated that some hydroxamate derivatives bind
many off-target metalloproteinases (MPs) that are not MMPs (10).
This may be related to the lack of selectivity of hydroxamic acid
for zinc over other divalent transition metals. The use of weaker
zinc chelating groups would reduce the strength of zinc binding,
and the optimization on the rest of the molecule should lead to
nanomolar inhibitors. This means, that the design of MMPIs should
be addressed individually in order to achieve selectivity.

The reported types of MMPIs include hydroxamates (succinyl
hydroxamates, sulfonamide hydroxamates, reverse hydroxamates,
naphthyl hydroxamates), non-hydroxamates (carboxylates and N-
carboxyalkyl ZBGs, thiol ZBGs, phosphorus-based ZBGs), and
miscellaneous natural products (7, 11).

Novel Zinc Binding Groups

In spite of the time and the money invested, and the numerous
groups interested on the development of MMPIs based on the

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