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

Biological Assays

According to the computational work, preliminary MMP-2
inhibition assays were carried out in duplicate for compounds 1n,
2m and 2n. Only 1n showed an interesting MMP-2 inhibitory activity.
Preliminary data show the decrease of the MMP-2 activity in the
presence of 1n, suggesting that this compound may be a promising
MMP-2 inhibitor. Unexpectedly, compounds 2m and 2n did not show
detectable MMP-2 inhibition. It has to be taken into account that
these two compounds are synthesis intermediates, so their character
as positive/negative AM modulators has not been determined yet.
AM affinity studies are currently in progress.

CONCLUSION

In this work we have carried out a theoretical study making
use of molecular mechanics, docking and molecular dynamics
techniques with the aim of demonstrating that positive modulators
of AM, may be acting as MMP-2 inhibitors as a possible mechanism
of action. This hypothesis has proven to be correct, according
to our theoretical studies, since almost all compounds evaluated
are able to bind MMP-2 in some of the conformations considered,
by chelating the zinc ion and interacting with key aminoacids in
the binding site of this enzyme. This ability and versatility to
coordinate Zn2+ ion seems to be a prominent feature of this family
of compounds not described before, to the best of our knowledge.
Additionally, the moderated electron donor character of the aryloxi
oxygen and the heterocyclic nitrogen, makes this family of
compounds an excellent alternative ZBG to hydroxamic acids, where
the pronounced zinc chelating properties may cause lack of
specificity. Biological evaluation of MMP-2 inhibition by some
selected compounds, selected according to the previous theoretical
work, has shown that compound 1n possesses an interesting
inhibitory activity.

Interestingly, the ZBG contained in this compound, does not
appear in any of the many MMP2 inhibitors reported in the
bibliography. This finding opens up an unexplored structural field

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