Cover image for Vol. 11 Issue 16

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.98

ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 76/253 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

July 19, 2013

VIP: Probing the S1' Site for the Identification of Non-Zinc-Binding MMP-2 Inhibitors

VIP: Probing the S1' Site for the Identification of Non-Zinc-Binding MMP-2 InhibitorsAntonella Di Pizio, Antonio Laghezza, Paolo Tortorella, Mariangela Agamennone*

Matrix metalloproteinases (MMPs) are zinc enzymes involved in several pathological states. Among them, MMP-2 is a particularly relevant therapeutic target because of its demonstrated role in cancer. Many MMP-2 inhibitors have been developed, but all of them contain an unselective zinc-binding group, which has been blamed for their side effects that ultimately hamper clinical trials. Inhibitors that avoid binding the zinc ion are known only for MMP-8, -12 and -13. These are of great interest because of their high selectivity and hence potential suitability as drugs.

In this work, a virtual screening protocol was expressly established in Dr. Mariangela Agamennone's research group at the University of Chieti (Italy) to use unexplored interactions in the MMP-2 binding site in identifying non-zinc-binding MMP-2 inhibitors. Enzyme inhibition assays revealed micromolar-level MMP-2 inhibitors, and activity data confirmed the team's working hypothesis regarding the inhibition of MMP-2 without binding the zinc ion. This work represents the first attempt to identify non-zinc-binding MMP-2 inhibitors.

The scaffold of these new MMP-2 hits affords an opportunity to develop more active and selective non-zinc-binding inhibitors with lower toxicity and higher selectivity than traditional ligands for this relevant target. This approach could pave the way for an effective anticancer treatment.

Received April 29, 2013; published online July 19, 2013, DOI: 10.1002/cmdc.201300186.

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