qHTS to Identify Small Molecule GUS Inhibitors

因此，该项目旨在筛选NCATS的化学文库，以针对一种新的、与疾病相关的微生物组靶点，以确定有希望的靶点，这些靶点可以进一步开发和优化为未来的共生药物。在为该项目建立合作框架后，针对GUSsome的关键同源物进行了优化、小型化和实施，以确定至少几种不同的化学系列作为命中。纯化的再合成和获得的粉末已用于命中验证，然后对多种细菌GUS酶的命中活性进行详细表征。对4个不同的化学系列进行药物化学sar驱动优化。一个关键的哌嗪片段似乎对活性至关重要，并可能在与酶亚状态形成加合物中起作用。与XTAL（薛定谔）签订了一份合同，以确定x射线研究指导基于结构的药物设计。来自三个系列的先导化合物也在Symberix的RgGUS（与筛选中使用的GUS H11G11密切相关）和基于细胞的分析中进行了表征。

As such, this project aims to screen the chemical libraries at NCATS against a novel, disease relevant microbiome target to identify promising hits that can be further developed and optimized into tomorrows symbiotic drugs. After establishing the collaborative framework for this project, a high-throughput assay against a key ortholog from the GUSsome was optimized, miniaturized, and implemented to identify at least several different chemical series as hits. Purified resynthesized and procured powders have been used for hit validation and followed by detailed characterization of hit activity against a diverse panel of bacterial GUS enzymes. Four different chemical series were followed up with medicinal chemistry SAR-driven optimization. A key piperazine moiety seems essential for activity and may play a role in forming an adduct with the enzyme substate. A contract with XTAL (Schrodinger) has been placed to determine X-ray studies to guide structure-based drug design. Lead compounds from three series are also being characterized at Symberix in RgGUS (closely related to H11G11, the GUS that used in the screen) and in cell-based assays.