GAPDH抑制剂的设计与合成及功能研究

GAPDH是细胞内功能众多的一种蛋白，近年来作为药物潜在靶标备受关注。本课题组首次发现了GAPDH与cADPR结合、并介导cADPR调控的细胞钙信号通路，本项目拟借助计算机辅助药物设计等策略，发展靶向GAPDH/cADPR结合位点的GAPDH抑制剂，并进行体内外活性、作用机制及成药性评价。本研究将拓展对GAPDH的生物学功能的认识，促进对GAPDH作为药物靶标的可能性的了解，为发展抗肿瘤药物以及药物靶标的确认奠定基础。研究内容主要包括：1基于虚拟筛选和实体化合物库筛选以及已知结构改造的活性化合物的发现；建立在细胞钙信号影响、表面等离子共振信号变化及肿瘤细胞增殖抑制的体外活性评价；发展合成方法、结构优化及构效关系研究；探讨抑制剂对细胞钙信号通路、PI3K/Akt/mTOR通路、氧化应激反应及肿瘤细胞侵袭迁移的影响；5) 从药效、药代及安全性方面初步考察抑制剂及靶点的成药性

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multi-functional protein in the cell. It has attracted much attention in recent years as a potential drug target. Our preliminary study for the first time found that GAPDH binded with cADPR, and mediated cellular calcium signaling pathway which was induced by cADPR. In this research, we will develop specific inhibitor which targets to GAPDH/cADPR binding site with the aid of computer aided drug design and other strategies. Meanwhile, in vitro and in vivo activities will be studied, molecular mechanism of action will be investigated, and the drugability will be evaluated. This research will expand the understanding of the biological function of GAPDH, have a deeper understanding for possibility of GAPDH as drug targets, and promote the development of GAPDH targeted antitumor drug candidates and drug target validation. The details of this research mainly includes: 1) the discovery of active compounds based on virtual screening, compound library assay, and structural modification of known compound. 2) in vitro screening based on calcium signaling, SPR and inhibition of proliferation of tumor cells. 3) development of synthetic strategy, structural optimization, and summarization of structure-activity relationship. 4) investigation of molecular mechanism from the aspects of effects on calcium pathway, PI3K/Akt/mTOR pathway, and Oxidative stress reaction. 5) the evaluation of drugability based on pharmacodynamics, pharmacokinetics and safety studies.