Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs).

Attolino, E.; Luchinat, C.; Dragoni, E.; Calderone, V.; Richichi, B.; Fragai, M.; Nativi, C.

doi:10.1016/j.ejmech.2010.09.057

Journal Article

PHPPUBDB-20356

Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs).

Attolino, E. ; Calderone, V. ; Dragoni, E. ; Fragai, M. ; Richichi, B. ; Luchinat, C. ; Nativi, C. ; DESY

2010
Elsevier Science Amsterdam [u.a.]

European journal of medicinal chemistry 45, 5919-5925 (2010) [10.1016/j.ejmech.2010.09.057]

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Abstract: N-arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative member of the family) with MMP-12 provided us with the basis to effectively design simple NNGH analogues with enhanced solubility in water. Following this approach, the sec-butyl residue, not directly involved in the binding with MMP, has been replaced with hydrophilic residues thus yielding new potent inhibitors soluble in water.

Keyword(s): Crystallography, X-Ray (MeSH) ; Matrix Metalloproteinase Inhibitors (MeSH) ; Models, Molecular (MeSH) ; Molecular Structure (MeSH) ; Nanostructures: chemistry (MeSH) ; Protease Inhibitors: chemical synthesis (MeSH) ; Protease Inhibitors: chemistry (MeSH) ; Protease Inhibitors: pharmacology (MeSH) ; Solubility (MeSH) ; Stereoisomerism (MeSH) ; Structure-Activity Relationship (MeSH) ; Sulfones: chemical synthesis (MeSH) ; Sulfones: chemistry (MeSH) ; Sulfones: pharmacology (MeSH) ; Water: chemistry (MeSH) ; Matrix Metalloproteinase Inhibitors ; Protease Inhibitors ; Sulfones ; Water