qHTS to Identify Small Molecule GUS Inhibitors

因此，该项目旨在根据一种新的与疾病相关的微生物组目标筛选NCATS的化学库，以确定有希望的目标，这些目标可以进一步开发和优化为未来的共生药物。在为这个项目建立了合作框架后，针对GUS Some的一个关键同源基因的高通量分析被优化、小型化并实施，以确定至少几个不同的化学系列为HITS。纯化、重新合成和采购的粉末已用于HIT验证，随后详细描述了HIT对各种细菌GUS酶的活性。对四个不同的化学系列进行了药物化学SAR驱动的优化。关键的哌嗪部分似乎是活性所必需的，并可能在与酶底物形成加合物的过程中发挥作用。已经与Xtal(薛定谔)签订了一份合同，确定X射线研究，以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(与屏幕上使用的GUS H11G11密切相关)和基于细胞的分析中得到表征。

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.