Human kallikrein 6 inhibitors with a para-amidobenzylanmine P1 group identified through virtual screening

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• 作者：Guyan Liang^a ; ^{guyan.liang@verizon.net} ; Xin Chen^a ; ^&dagger ; ; ^{xin.chen@sanofi.com} ; Suzanne Aldous^b ; Su-Fen Pu^c ; Shujaath Mehdi^d ; Elaine Powers^e ; Tianhui Xia^f ; ^&Dagger ; ; Rachel Wang^f
• 关键词：Serine protease ; MS ; Human kallikrein 6 ; Inhibitor ; Molecular modeling ; Virtual screening ; X-ray crystallography
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2450-2455
• 文件大小：1486 K

摘要

A series of hK6 inhibitors with a para-amidobenzylamine P1 group and a 2-hydroxybenzamide scaffold linker was discovered through virtual screening. The X-ray structure of hK6 complexed with compound 9b was determined to a resolution of 1.68 脜. The tertiary folding of the hK6 complexed with the inhibitor is conserved relative to the structure of the apo-protein, whereas the interaction between hK6 and the inhibitor is consistent with both the SAR and the in silico model used in the virtual screening.