Computational
Characterization of Ketone–Ketal
Transformations at the Active Site of Matrix Metalloproteinases
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Abstract
We modeled the first steps of hydrolysis
reactions of a natural
oligopeptide substrate of matrix metalloproteinase MMP-2 as well as
of a substrate analogue. In the latter, the scissile amide group is
substituted by a ketomethylene group which can be transformed to the
ketal group upon binding of this compound to the enzyme active site.
According to our quantum mechanical–molecular mechanical (QM/MM)
calculations, the reaction of the ketone–ketal transformation
proceeds with a low energy barrier (3.4 kcal/mol) and a high equilibrium
constant (10<sup>4</sup>). The reaction product with the ketal group
formed directly at the active site of the enzyme works as an inhibitor
that chelates the zinc ion. On the other hand, the oligopeptide mimetic
retains molecular groups responsible for binding of this compound
to the enzyme active site. This example illustrates a strategy to
design MMP inhibitors <i>in situ</i> by using data on binding
specificity of substrates to a particular type of MMP and details
of the reaction mechanism