Oxaprozin: a new hope in the modulation of matrix metalloproteinase 9 activity

The aim of this study was to investigate the ability of oxaprozin, a nonsteroidal anti‐inflammatory drug, to modulate the activity of matrix metalloproteinase 9 (MMP‐9), a zinc dependent endopeptidase involved in a wide range of physiological and pathological events. The interaction between oxaprozin and MMP‐9 was firstly investigated in silico, and the potential inhibitory activity and the possible mechanism of the ligand‐enzyme interaction were subsequently investigated in vitro.These data provide the molecular basis for the potential use of oxaprozin as modulator of MMP‐9 activity and, besides this, would support the development of more selective MMP‐9 inhibitors.

Abstract

Oxaprozin (4,5‐diphenyl‐2‐oxazolepropionic acid) is a nonsteroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP‐9), a zinc dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling.

The interaction between oxaprozin and MMP‐9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP‐9 and the possible mechanism of the ligand‐enzyme interaction were investigated in vitro.

Taking into account the in silico findings, MMP‐9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl ring interact with the S1′ inhibitor binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP‐9. These observations sound particularly interesting if we consider the pathological role of MMP‐9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP‐9 function.

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