PNU-107859, an important representative structure in a novel class of matrix metalloproteinases (MMP) inhibitors known as thiadiazoles, was found to be quickly eliminated from rats. A major metabolite (approximately 10% of total dose) was found to be present in the bile of rats. The metabolite in question was isolated and purified from the bile fluids collected from six cannulated rats. From a total of approximately 75 mg of PNU-107859 administered to rats, 3.3 mg of the metabolite was recovered. The NMR and mass spectrometry results indicated that the metabolite is a glucuronide conjugate (1-deoxy-1beta-substituted D-glucopyranosiduronic acid) of the intact drug. Furthermore, the UV, MS, and NMR data established that the conjugate is located at the nitrogen alpha to the thiocarbonyl of the thiadiazole ring.

01 Jan 1999·Journal of Biomolecular NMRQ3 · BIOLOGY

Dynamics of stromelysin/inhibitor interactions studied by 15N NMR relaxation measurements: comparison of ligand binding to the S1-S3 and S'1-S'3 subsites.

Q3 · BIOLOGY

Article

Author: Yuan, Peng ; Marshall, Vincent P. ; Stockman, Brian J. ; Poorman, Roger A. ; Petzold, Gary L.

This report describes the backbone amide dynamics of the uniformly 15N labeled catalytic domain of human stromelysin complexed to PNU-99533, a hydroxamate-containing ligand that binds to the S'1-S'3 region (right side) of the stromelysin active site, and to PNU-107859 and PNU-142372, both thiadiazole-containing ligands that bind to the S1-S3 region (left side) of the stromelysin active site. 15N R1, R2 and NOE NMR relaxation measurements were recorded and analyzed for each complex. Different dynamic behaviors were observed for stromelysin complexed to the two classes of ligands, indicating that it may be possible to use protein dynamics to distinguish between different binding orientations. In the absence of bound ligand at the S1-S3 subsites, the S1-S3 residues were found to be relatively rigid. In contrast, the S'1-S'3 subsites were found to be flexible in the absence of interactions with ligand. The relative rigidness of the S1-S3 subsites may be responsible for MMP binding specificity by discriminating between ligands of different shapes. By contrast, the inherent flexibility of the S'1-S'3 subsites allows structural rearrangement to accommodate a broad range of incoming substrates or inhibitors. Similarities and differences in dynamics observed for each complex provide insights into the interactions responsible for protein-ligand recognition. The relevance of protein dynamics to structure-based drug design is discussed.

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Indication	Highest Phase	Country/Location	Organization	Date
Arthritis	Discovery	US	Pharmacia & Upjohn, Inc.	-
Carcinoma	Discovery	US	Pharmacia & Upjohn, Inc.	-

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