標題: Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries
作者: Hsu, Kai-Cheng
Cheng, Wen-Chi
Chen, Yen-Fu
Wang, Hung-Jung
Li, Ling-Ting
Wang, Wen-Ching
Yang, Jinn-Moon
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
公開日期: 29-二月-2012
摘要: 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 (IC50 < 8.0 mu M) 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.
URI: http://dx.doi.org/e32142
http://hdl.handle.net/11536/16135
ISSN: 1932-6203
DOI: e32142
期刊: PLOS ONE
Volume: 7
Issue: 2
結束頁: 
顯示於類別:期刊論文


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