Core site-moiety maps reveal inhibitors and binding mechanisms of orthologous proteins by screening compound libraries

Kai Cheng Hsu, Wen Chi Cheng, Yen Fu Chen, Hung Jung Wang, Ling Ting Li, Wen Ching Wang, Jinn Moon Yang

Research output: Contribution to journalArticle

16 Citations (Scopus)


Members of protein families often share conserved structural subsites for interaction with chemically similar moieties despite low sequence identity. We propose a core site-moiety map of multiple proteins (called CoreSiMMap) to discover inhibitors and mechanisms by profiling subsite-moiety interactions of immense screening compounds. The consensus anchor, the subsite-moiety interactions with statistical significance, of a CoreSiMMap can be regarded as a "hot spot" that represents the conserved binding environments involved in biological functions. Here, we derive the CoreSiMMap with six consensus anchors and identify six inhibitors (IC 50<8.0 μM) of shikimate kinases (SKs) of Mycobacterium tuberculosis and Helicobacter pylori from the NCI database (236,962 compounds). Studies of site-directed mutagenesis and analogues reveal that these conserved interacting residues and moieties contribute to pocket-moiety interaction spots and biological functions. These results reveal that our multi-target screening strategy and the CoreSiMMap can increase the accuracy of screening in the identification of novel inhibitors and subsite-moiety environments for elucidating the binding mechanisms of targets. © 2012 Hsu et al.

Original languageEnglish
Article numbere32142
JournalPLoS One
Issue number2
Publication statusPublished - Feb 29 2012
Externally publishedYes


ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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