Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs).
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.
Attolino
Emanuele
E
ProtEra s.r.l. viale delle Idee, 22 I-50019 Sesto F.no (FI), Italy.
Calderone
Vito
V
Dragoni
Elisa
E
Fragai
Marco
M
Richichi
Barbara
B
Luchinat
Claudio
C
Nativi
Cristina
C
D018360:Crystallography, X-Ray; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013450:Sulfones; D014867:Water