College of Life Sciences, Northwest University, Xi'an 710069, China.
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
J Med Chem. 2021 Apr 8;64(7):4196-4205. doi: 10.1021/acs.jmedchem.1c00123. Epub 2021 Mar 30.
Natural products have failed to meet the urgent need for drug discovery in recent decades due to limited resources, necessitating new strategies for re-establishing the key role of natural products in hit screening. This work introduced DNA-encoding techniques into the synthesis of phenolic acid-focused libraries containing 32 000 diverse compounds. Online selection of the library using immobilized angiotensin II type I receptor (ATR) resulted in seven phenolic acid derivatives. The half-maximal concentration (IC) of hit 1 for the right shift of the [I]-Sar1-AngII competition curve was 19.6 nM. Pharmacological examination of renovascular hypertensive rats demonstrated that hit 1 significantly lowered the blood pressure of the animals without changing their heart rates. These results were used to create a general strategy for rapid and unbiased discovery of hits derived from natural products with high throughput and efficiency.
天然产物在最近几十年未能满足药物发现的迫切需求，由于资源有限，需要新的策略来重新确立天然产物在命中筛选中的关键作用。这项工作将 DNA 编码技术引入到合成以酚酸为重点的文库中，该文库包含 32000 种不同的化合物。使用固定化血管紧张素 II 型 1 型受体 (ATR) 在线选择文库，得到了 7 种酚酸衍生物。命中 1 化合物使 [I]-Sar1-AngII 竞争曲线右移的半最大浓度 (IC) 为 19.6 nM。对肾血管性高血压大鼠的药理学研究表明，命中 1 化合物可显著降低动物的血压，而不改变其心率。这些结果被用来创建一种快速、无偏的高通量、高效率的天然产物命中发现的一般策略。
