Page 81 - 73_03

MARIO A. GARCÍA Y COLS. AN. R. ACAD. NAC. FARM.

MMPI has been reported to date. A selective inhibitor of MMP-9 has
been obtained using a thiadiazine scaffold, and a similar ZBG, the
thiadiazole thione, has been analyzed in the catalytic site of MMP-
3. Browner et al. investigated the differences among three identical
compounds bearing different ZBGs (hydroxamate, carboxylate and
sulfodiimines, crystalized in complex with MMP-7), concluding that
the binding potency differences among them were consequence of
the geometry adopted by the ZBG chelating the zinc atom (14).
Another theoretical study showed that pyridone analogues can
behave as ZBGs as well. Also, the aminomethyl benzimidazole group
has been described as a ZBG with micromolar activity.

Others ZBGs not described by Rao et al. include
hydroxysulfonamides (15), hydroxyureas (16), dipicolylamines
(17), ß-lactams (18) and squaric acids (18). Additionally, 3D
structures of many MMP-Inhibitor complexes, solved either by X-
ray diffraction or NMR techniques, have shown that the different
chelating ZBGs coordinate catalytic zinc ion most frequently in a
pentacoordinated way (19).

Binding of MMPIs is not only explained by coordination of the
ligand ZBG to the catalytic zinc ion. Binding and, more importantly,
selectivity, have been addressed by interactions with key residues
belonging to different subsites, specially the S1’ region. Thus,
extensive hydrophobic interactions between the lipophilic moieties
of the ligands and the S1’ pocket can be largely responsible for the
binding potencies (20).

Since a combination of factors, including the nature of ZBG,
scaffolds and side chains that occupy different subsites, influence
the selectivity and that the structural differences between MMPs
take place mainly in the S1’ sub-site, all these features will have to
be taken into account in order to design compounds with the desired
selectivity.

Working Hypothesis: Can AM positive modulators be MMP2
inhibitors?

Matrix metalloproteinases are responsible of degrading several
components of the extracellular matrix (ECM), among other proteins

710