Matrix metalloproteinases (MMPs) are zinc enzymes responsible for the degradation of the
extracellular matrix. With this function, MMPs are involved in many physiological processes, but also
in many pathological states. MMP-13 is implicated in the degradation of type II collagen, the main
structural protein of articular cartilage, contributing to the development of osteoarthritis and inflammatory
diseases. In the last years, a new generation of potent and selective MMP inhibitors (MMPIs) has been identified
and classified as non-zinc-binding inhibitors (NZBIs). Several MMP-13 NZBIs have been developed and crystallographically
determined in complex with the enzyme. Here, we provide a detailed review of the current knowledge about this
class of MMP-13 inhibitors and, by using computational procedures, we highlight the molecular determinants that are
needed for the binding process. In particular, FLAP, a program based on GRID molecular interaction fields, was used to
analyze the ligand-protein interactions: molecular shape and hydrogen bond acceptor groups strongly influence the binding
according to the ligand-based modeling, while the aromatic interactions are better identified by the structure-based
study. The complementary results can be combined in a high performance model, showing the effectiveness of molecular
interaction field based approaches to search for novel MMP-13 NZBIs.
Keywords: Drug design, Binding pocket, GRID, MMP-13, Molecular modeling, Molecular similarity, Non-zinc-binding inhibitors.
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