qHTS to Identify Small Molecule GUS Inhibitors

因此，该项目旨在针对一种新的疾病相关微生物组靶标筛选NCATS的化学文库，以确定可以进一步开发和优化为明天的共生药物的有希望的命中。在建立了该项目的合作框架后，针对GUSsome的关键直系同源物的高通量测定被优化、小型化并实施，以识别至少几个不同的化学系列作为命中物。纯化的再合成和采购的粉末已用于命中验证，然后详细表征针对不同细菌GUS酶组的命中活性。四个不同的化学系列进行了后续与药物化学SAR驱动的优化。一个关键的哌嗪部分似乎是必不可少的活动，并可能发挥作用，形成加合物与酶底物。已与XTAL（薛定谔）签订合同，以确定X射线研究来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）和基于细胞的测定中进行了表征。

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.