Columbia University Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
The Center for Experimental Therapeutics & Pharmacoinformatics, Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
Future Med Chem. 2021 Jul;13(13):1091-1103. doi: 10.4155/fmc-2021-0056. Epub 2021 Jun 3.
This study investigated our Enzymelinks, COX-2-10aa-mPGES-1 and COX-2-10aa-PGIS, as cellular cross-screening targets for quick identification of lead compounds to inhibit inflammatory PGE biosynthesis while maintaining prostacyclin synthesis. We integrated virtual and wet cross-screening using Enzymelinks to rapidly identify lead compounds from a large compound library. From 380,000 compounds virtually cross-screened with the Enzymelinks, 1576 compounds were identified and used for wet cross-screening using HEK293 cells that overexpressed individual Enzymelinks as targets. The top 15 lead compounds that inhibited mPGES-1 activity were identified. The top compound that specifically inhibited inflammatory PGE biosynthesis alone without affecting COX-2 coupled to PGI synthase (PGIS) for PGI biosynthesis was obtained. Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.
本研究以我们的 Enzymelink（COX-2-10aa-mPGES-1 和 COX-2-10aa-PGIS）为细胞交叉筛选靶点，旨在快速鉴定抑制炎症性 PGE 生物合成同时维持前列环素合成的先导化合物。我们使用 Enzymelink 整合虚拟和湿实验交叉筛选，从大型化合物库中快速鉴定先导化合物。通过虚拟筛选与 Enzymelink 交叉筛选了 380000 种化合物，鉴定出 1576 种化合物，并用于以过表达单个 Enzymelink 为靶点的 HEK293 细胞的湿实验交叉筛选。鉴定出抑制 mPGES-1 活性的前 15 种先导化合物。获得了一种能够特异性抑制炎症性 PGE 生物合成而不影响与 PGI 合酶（PGIS）偶联的 COX-2 的化合物。Enzymelink 技术可以极大地推动环氧化酶通路靶向药物发现的进展。
