Elevated expression of periostin in human osteoarthritis cartilage and its potential role in matrix degradation via MMP-13

Attur, Mukundan; Yang, Qing; Shimada, Kohei; Tachida, Yuki; Nagase, Hiroyuki; Mignatti, Paolo; Statman, Lauren Y.; Palmer, Glyn D.; Kirsch, Thorsten; Beier, Frank; Abramson, Steven B.

doi:10.1016/j.joca.2015.02.868

Cited by 1 publication

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“…As the most efficient contributor to degeneration of type II collagen within its superfamily of zinc-dependant endopeptidases, matrix metalloproteinase-13 (MMP-13) is a highly validated target for the treatment of diseases based on tissue degradation [ 1 , 2 , 3 , 4 , 5 ]. Unregulated MMP activity can lead to a variety of diseases such as tumor growth and metastasis, periodontal disease and osteoarthritis (OA) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies

Fischer¹,

Riedl²

2016

IJMS

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Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91).

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