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SJTU Research Group discovered STAT3 Allosteric Modulator via Drug design method

May 23, 2018      Author: Shanghai Jiaotong University School of Medicine

The research group led by Zhang Jian of SJTU School of Medicine developed a targeted allosteric screening design method based on protein structure, and discovered new allosteric sites and allosteric modulator of STAT3. On May 11, the world-famous journal Nucleic Acids Research published the research group's paper, titled with AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses, and demonstrated that AlloFinder, the newly developed allosteric drug design technology, was used to discover the new allosteric sites and allosteric modulator of STAT3 at the C end of the coiled-coil domain, which breaks a new path for antineoplastic drugs targeting at STAT3.

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Professor Zhang Jian of SJTU School of Medicine is the corresponding author of this paper, and joint efforts were also made by Academician Chen Guoqiang of SJTU School of Medicine and Researcher Wang Renxiao of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

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Allostery tweaks innumerable biological processes and plays a fundamental role in human disease and drug discovery. Exploration of allostery has thus been regarded as a crucial requirement for research on biological mechanisms and the development of novel therapeutics. Here, based on our previously developed allosteric data and methods, we present an interactive platform called AlloFinder that identifies potential endogenous or exogenous allosteric modulators and their involvement in human allosterome. AlloFinder automatically amalgamates allosteric site identification, allosteric screening and allosteric scoring evaluation of modulator-protein complexes to identify allosteric modulators, followed by allosterome mapping analyses of predicted allosteric sites and modulators in human proteome. This web server exhibits prominent performance in the reemergence of allosteric metabolites and exogenous allosteric modulators in known allosteric proteins. Specifically, AlloFinder enables identification of allosteric metabolites for metabolic enzymes and screening of potential allosteric compounds for disease-related targets. Significantly, the feasibility of AlloFinder to discover allosteric modulators was tested in a real case of signal transduction and activation of transcription 3 (STAT3) and validated by mutagenesis and functional experiments. Collectively, AlloFinder is expected to contribute to exploration of the mechanisms of allosteric regulation between metabolites and metabolic enzymes, and to accelerate allosteric drug discovery. The AlloFinder web server is freely available to all users at http://mdl.shsmu.edu.cn/ALF/.

 

Translated by Huang Yiqing   Reviewed by Wang Bingyu