Jump to main content
Jump to site search

Issue 4, 2014
Previous Article Next Article

More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors

Author affiliations

Abstract

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–activity 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.

Graphical abstract: More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors

Back to tab navigation

Supplementary files

Publication details

The article was received on 23 Jan 2014, accepted on 04 Feb 2014 and first published on 05 Feb 2014


Article type: Concise Article
DOI: 10.1039/C4MD00030G
Author version
available:
Download author version (PDF)
Citation: Med. Chem. Commun., 2014,5, 507-511

  •   Request permissions

    More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors

    W. Li, X. Wan, F. Zeng, Y. Xie, Y. Wang, W. Zhang, L. Li and N. Huang, Med. Chem. Commun., 2014, 5, 507
    DOI: 10.1039/C4MD00030G

Search articles by author

Spotlight

Advertisements