In silico screening for PTPN22 inhibitors: active hits from an inactive phosphatase conformation.
In silico screening for PTPN22 inhibitors: active hits from an inactive phosphatase conformation.
复制标题
DOI：
10.1002/cmdc.200800375
复制
发表时间：
2009-03
期刊：
影响因子：
3.4
通讯作者：
Tautz, Lutz
中科院分区：
文献类型：
--
作者：
Wu, Shuangding;Bottini, Massimo;Rickert, Robert C.;Mustelin, Tomas;Tautz, Lutz
A gain-of-function mutant of the lymphoid phosphatase Lyp (PTPN22) has recently been implicated with type 1 diabetes and other autoimmune diseases, suggesting that small-molecule inhibitors of Lyp could be useful for the treatment of autoimmunity. Virtual ligand screening (VLS) was applied in the search for hit compounds. Two different docking algorithms, FlexX and ICM, were used to screen a library of ‘drug-like’ molecules against two different 3D structures, representing Lyp’s catalytic site in both the inactive ‘open’ and active ‘closed’ conformation. Top scoring compounds of each VLS run were tested for their inhibitory activity against recombinant Lyp. Interestingly, VLS with both active and inactive conformation yielded very potent hits with IC50 values in the sub and low micromolar range. Moreover, many of these hits showed high docking scores only with one conformation. This was for instance the case with several 2-benzamidobenzoic acid derivatives, which specifically docked to the inactive open form. Tryptophan fluorescence measurements further supported a binding mode, in which these compounds seem to stabilize the phosphatase in its inactive conformation.
登录
查看更多内容
影响因子：
30.8
作者：
Vang, T;Congia, M;Bottini, N
通讯作者：
Bottini, N
影响因子：
9.8
作者：
Kyogoku, C;Langefeld, CD;Behrens, TW
通讯作者：
Behrens, TW
影响因子：
5.8
作者：
Arnold, K;Bordoli, L;Schwede, T
通讯作者：
Schwede, T
DOI：
10.1073/pnas.0706233104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Yu, Xiao;Sun, Jin-Peng;Zhang, Zhong-Yin
通讯作者：
Zhang, Zhong-Yin
影响因子：
5.6
作者：
Rarey, M;Kramer, B;Klebe, G
通讯作者：
Klebe, G