University of Ljubljana, Faculty of Pharmacy, Slovenia.
University of Ljubljana, Faculty of Pharmacy, Slovenia.
Bioorg Med Chem Lett. 2022 Oct 1;73:128915. doi: 10.1016/j.bmcl.2022.128915. Epub 2022 Jul 30.
Screening of DNA-encoded libraries is an emerging technology for discovering hits against protein targets. With the recent launch of the DELopen platform, a facile screening of 4.4 billion compounds is available to accelerate the drug discovery process. Here we report an affinity-based screening of the DELopen library for the first time. The screening was performed against two bacterial enzymes of the peptidoglycan biosynthetic pathway, N-acetylglucosamine-enolpyruvyl transferase (MurA) and d-alanine:d-alanine ligase (DdlB). Several binders were obtained and selected for off-DNA synthesis. Hits with confirmed inhibitory potency were deconstructed into smaller fragments. In this way, two new MurA inhibitors with antibacterial activity were obtained and are available for further optimization.
DNA 编码文库筛选是一种新兴的技术，可用于发现针对蛋白质靶标的命中物。随着 DELopen 平台的最近推出，可方便地筛选 44 亿种化合物，从而加速药物发现过程。在这里，我们首次报道了针对 DELopen 文库的基于亲和力的筛选。筛选针对肽聚糖生物合成途径中的两种细菌酶，N-乙酰葡萄糖胺烯醇丙酮酸转移酶（MurA）和 D-丙氨酸：D-丙氨酸连接酶（DdlB）进行。获得了几个结合物，并选择进行 DNA 外合成。具有确认的抑制效力的命中物被分解成较小的片段。通过这种方式，获得了两种具有抗菌活性的新 MurA 抑制剂，可进一步优化。
