Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization

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• 作者：Valeria La Pietra^a ; ¹ ; Luciana Marinelli^a ; ¹ ; ^{lmarinel@unina.it} ; Sandro Cosconati^b ; Francesco Saverio Di Leva^c ; Elisa Nuti^d ; Salvatore Santamaria^d ; ^e ; Isabella Pugliesi^d ; Matteo Morelli^d ; Francesca Casalini^d ; Armando Rossello^d ; Concettina La Motta^d ; Sabrina Taliani^d ; Robert Visse^e ; Hideaki Nagase^e ; Federico da Settimo^d ; Ettore Novellino^a ; ¹
• 关键词：MMPs ; Virtual screening ; Molecular docking ; Osteoarthritis ; Cancer
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January, 2012
• 年：2012
• 卷：47
• 期：Complete
• 页码：143-152
• 全文大小：740 K

文摘

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in?vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC₅₀ in the low ¦ÌM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.