肿瘤细胞生长抑制剂Gemmacolides的靶标研究

Target research is the key scientific question of marine natural products. Thus, most of the novel marine bioactive natural products are hardly processed to clinical drug. Gemmacolides, found by our group, are potent tumor cell growth inhibitors with the structure of Briarane diterpenes, which is much better than bleomycin. However, its target is still unknown. In order to solve this question, we would love to carry out the target research of Gemmacolides by the methods of chemical biology and chemical informatics. (i) The inverse virtual screening (IVS) will be applied to screen the targets of Gemmacolides form the 300 published cancer related targets; (ii) If the target is an unpublished one, we would love to semi-synthesize molecular probes of Gemmacolides and establish the target screening method via photolabeling (PAL), click chemistry (CC) and activity-based protein profiling (ABPP). Through this case, we would love to establish an effective methodology and research strategy on target identification of marine active products. And this strategy takes very important role on promoting the identification of marine lead compounds and the research on marine drugs.

靶标研究是海洋药物先导物研究的关键科学问题，很多结构新颖的活性海洋天然产物受制于此而迟滞了其后续的新药研究进程。Gemmacolides是本课题组发现的高活性Briarane二萜肿瘤生长抑制剂，活性显著高于博来霉素，但其作用靶标尚不明确。本研究拟将化学生物学与化学信息学紧密结合开展对Gemmacolides作用靶标的研究：运用反向虚拟筛选(IVS)技术将Gemmacolides与结构已知的300余种肿瘤相关蛋白进行计算机拟合，对具有高亲和度的靶点进行生物学验证，从已知蛋白中发现作用靶标；合成Gemmacolides分子探针，运用光化学(PAL)及点击化学(CC)技术、结合活性导向的蛋白谱技术(ABPP)进行全新靶标的发现。通过对Gemmacolides作用靶标的研究，构建海洋活性物质靶标发现的有效技术方法及研究策略，对于促进海洋药物先导化合物的发现、推动海洋药物研究进程具有重要意义。

靶标研究是海洋药物先导物研究的关键科学问题，很多结构新颖的活性海洋天然产物受制于此而迟滞了其后续的新药研究进程。Gemmacolides是本课题组发现的高活性Briarane二萜肿瘤生长抑制剂，但作用靶标尚不明确。本研究通过将化学生物学与化学信息学紧密结合开展对Gemmacolides作用靶标的研究：运用自动化脚本式反向虚拟筛选技术将Gemmacolides与结构已知的300余种肿瘤相关蛋白进行计算机拟合，对具有高亲和度的靶点进行生物学验证，从已知蛋白中发现作用靶标Rack1；以查尔酮为天然模板，合成分子探针，构建了光化学(PAL)及点击化学(CC)技术、结合活性导向的蛋白谱技术(ABPP)全新靶标研究方法。通过对以上研究，构建海洋活性物质靶标发现的有效技术方法及研究策略，对于促进海洋药物先导化合物的发现、推动海洋药物研究进程具有重要意义。