期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 19, 页码 5487-5505出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.025
关键词
Matrix metalloproteinase; MMP-13; Thieno[2,3-d]pyrimidin-4-one; Osteoarthritis; OA; X-ray crystallography; Structure-based drug design
On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1 '' hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M. (C) 2014 Published by Elsevier Ltd.
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