Abstract

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in several pathological states. Among them, MMP-2 is a relevant therapeutic target because of its role in cancer development and progression. Many MMP inhibitors (MMPIs) have been discovered over the last 30 years, and the majority of them contain a functional group that binds the zinc ion (zinc-binding group; ZBG). Unfortunately, no MMPIs have reached the market yet, owing to toxic effects due to unselective interactions of the ZBG. The new generation of MMPIs that do not bind the zinc ion could overcome problems of selectivity and toxicity, but have so far been developed only for MMP-8, -12, and -13. In this work, a virtual screening protocol was established by combining ligand- and structure-based methods to identify non-zinc-binding MMP-2 inhibitors using a new-generation MMP-8 inhibitor as a probe to find unexplored interactions in the MMP-2 S1’ site. The screening allowed the identification of micromolar MMP-2 inhibitors that putatively avoid binding the zinc ion, as demonstrated by docking calculations. The LIA model, built to correlate predicted and experimental binding energies of the identified nonzinc- binding MMP-2 hits, underpins the reliability of the predicted docking poses.

Autore Pugliese

• Laghezza Antonio , Tortorella Paolo

Tutti gli autori

• LAGHEZZA A.;TORTORELLA P.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2013

ISSN

1860-7179

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

14

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

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Codici ASJC

Non Disponibile