Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group
详细信息 查看全文
- 作者：Guyan Liang ; Xin Chen ; Suzanne Aldous ; Su-Fen Pu ; Shujaath Mehdi ; Elaine Powers ; Andrew Giovanni ; Sathapana Kongsamut ; Tianhui Xia ; Ying Zhang ; Rachel Wang ; Zhongli Gao ; Gregory Merriman ; Larry R. McLean ; Isabelle Morize
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：3
- 期：2
- 页码：159-164
- 全文大小：398K
- 年卷期：v.3,no.2(February 9, 2012)
- ISSN：1948-5875
文摘
A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 脜, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S鈥?pocket.