{"id":413,"date":"2014-03-12T12:07:14","date_gmt":"2014-03-12T04:07:14","guid":{"rendered":"http:\/\/www.huanglab.org.cn\/wordpress\/?p=413"},"modified":"2014-03-12T12:14:59","modified_gmt":"2014-03-12T04:14:59","slug":"more-than-just-a-gpcr-ligand-structure-based-discovery-of-thioridazine-derivatives-as-pim-1-kinase-inhibitors","status":"publish","type":"post","link":"https:\/\/www.huanglab.org.cn\/wordpress\/?p=413","title":{"rendered":"More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors"},"content":{"rendered":"<p><a href=\"http:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2014\/03\/GA.gif\"><img loading=\"lazy\" class=\"alignnone size-full wp-image-414\" alt=\"More than just a GPCR ligand\" src=\"http:\/\/www.huanglab.org.cn\/wordpress\/wp-content\/uploads\/2014\/03\/GA.gif\" width=\"250\" height=\"189\" \/><\/a><\/p>\n<p><a title=\"MedChemComm\" href=\"http:\/\/pubs.rsc.org\/EN\/content\/articlelanding\/2014\/md\/c4md00030g\" target=\"_blank\">More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors<\/a><\/p>\n<p>Wei Li,<sup>ab<\/sup> Xiaobo Wan,<sup>b<\/sup> Fanqi Zeng,<sup>b<\/sup> Yuting Xie,<sup>b<\/sup> Yanli Wang,<sup>b<\/sup> Wei Zhang,<sup>b<\/sup> Li Li<sup>b<\/sup> and Niu Huang*<sup>ba<\/sup><\/p>\n<p>*Corresponding authors<br \/>\n<sup>a<\/sup>Graduate Program in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China<br \/>\n<sup>b<\/sup>National Institute of Biological Sciences, Beijing No. 7 Science Park Road, Zhongguancun Life Science Park, Changping, Beijing 102206, China<\/p>\n<p>Pim-1 kinase is a serine\/threonine kinase which plays an important role in cell proliferation and differentiation. The Pim-1 kinase expression is elevated in leukemia and prostate cancer. Accordingly, we employed a structure-based hierarchical virtual screening approach to identify potential unknown Pim-1 kinase activity for existing drugs. Among the LOPAC library of pharmacologically active compounds, one top-ranked drug molecule thioridazine, a well-known antipsychotic agent which exerted its biological function as a dopamine receptor antagonist, showed low micromolar activity in the Pim-1 enzymatic assay. We determined the co-crystal structure of thioridazine bound with Pim-1 kinase, and defined the key elements of the pharmacophore by analyzing the structure\u2013activity relationship of thioridazine analogues. In addition, we also assessed our pharmacophore by successfully predicting the Pim-1 activity of the selective Akt inhibitor, 10-DEBC. Our discovery of the unknown Pim-1 inhibitory activity of thioridazine and 10-DEBC might provide novel insights into understanding their molecular mechanism of action, and inspire the computation-driven multiple-target drug discovery.<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors Wei Li,ab Xiaobo Wan,b Fanqi Zeng,b Yuting Xie,b Yanli Wang,b Wei Zhang,b Li Lib and Niu Huang*ba *Corresponding authors aGraduate Program in Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China bNational Institute of Biological Sciences, [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"ngg_post_thumbnail":0},"categories":[],"tags":[],"_links":{"self":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/413"}],"collection":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=413"}],"version-history":[{"count":10,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/413\/revisions"}],"predecessor-version":[{"id":423,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/413\/revisions\/423"}],"wp:attachment":[{"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=413"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=413"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.huanglab.org.cn\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=413"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}