期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 13, 页码 2713-2719出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.04.027
关键词
In silico; Joint pharmacophore space; Ensemble docking; LRRK2; Inhibitor
资金
- University of Houston
Joint pharmacophore space (JPS), ensemble docking and sequential JPS-ensemble docking were used to select three panels of compounds (10 per panel) for evaluation as LRRK2 inhibitors. These computational methods identified four LRRK2 inhibitors with IC50 values <12 mu M. The sequential JPS-ensemble docking predicted the majority of active hits. One of the inhibitors (Z-8205) identified using this method was also found to inhibit the G2019S mutant of LRRK2 25-fold better than wild-type enzyme. This bias for the G2019S mutant is proposed to arise from an interaction with S2019 in this form of the enzyme. In addition, Z-8205 was found to only inhibit one other kinase when profiled against a panel of 97 kinases at 10 mu M. (C) 2015 Elsevier Ltd. All rights reserved.
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