Core site-moiety maps reveal inhibitors and binding mechanisms of orthologous proteins by screening compound libraries |
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Authors: | Hsu Kai-Cheng Cheng Wen-Chi Chen Yen-Fu Wang Hung-Jung Li Ling-Ting Wang Wen-Ching Yang Jinn-Moon |
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Affiliation: | Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan. |
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Abstract: | 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. |
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