Abstract
Different common drugs (Meloxicam, Tenoxicam and Piroxicam, and sodium alendronate) were tested both experimental and theoretically as inhibitors of interstitial human collagenase, also known as matrix metalloproteinase 1 (MMP-1). The in vitro collagenase activity, alone and in the presence of inhibitors, was quantified by the reaction with a fluorescent synthetic substrate and measuring the change of emission. Collagenase-inhibitor interaction was studied theoretically by computational calculations. Three among the four tested substances showed moderate inhibiting activity against the human collagenase.
Highlights
The metalloproteinases of the conjunctive matrix, known as matrixins or MMP, constitute a subgroup of the zinc-endoproteases produced by the conjunctive tissue. These enzymes participate in the initial events that result in tissue degradation, both in physiologic and pathologic conditions. They are divided in five groups: 1. collagenases that hydrolyze the collagen, protein resistant to most of the proteases; 2. gelatinases, named because they hydrolyze denatured collagen, known as type IV collagenases, for they degrade native collagen type IV; 3. stromelysins, originally described as proteoglycanases, but that possess a reasonably wide proteolytic activity; 4
Kinetic parameters for the human collagenase were obtained from the plot of fluorescent emission at 394 nm versus Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 concentration in μmol/l
We observed a similar activating effect of the alendronate upon the activity of the collagenase produced by the bacterium Clostridium histolyticum, one of the causative agents of gas gangrene [34]
Summary
The metalloproteinases of the conjunctive matrix, known as matrixins or MMP (the acronym of Matrix Metallo Proteinase), constitute a subgroup of the zinc-endoproteases produced by the conjunctive tissue. Metalloproteases from connective tissue of mammals, MMPs, have in common two ions of zinc, one located in the enzyme active site, involved in the catalytic process, and the other with structural function, similar to calcium ions in these enzymes. An example of the first type is the molecule of water binding to zinc in the active enzyme, which dissociates under the polarizing effect of Zn2+ , even in environments with pH values not very high, generating a hydroxyl able to attack other molecules. The mechanism of catalysis by matrix metalloproteases, as the human collagenase, is an example of the second type of mechanism In this case, the hydrolysis of the amide (peptidic bond) begins by attack of the zinc, as a Lewis acid, on the carbonylic oxygen, polarizing the carbonyl and facilitating the attack of its carbon by the hydroxyl of water linked to zinc. The great advantage in selecting drugs already used in other pathologies is the previous knowledge of their toxicity and safety, checked by the acquired clinical experience
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