Engineering 'Enzymelink' for screening lead compounds to inhibit mPGES-1 while maintaining prostacyclin synthase activity.
Engineering 'Enzymelink' for screening lead compounds to inhibit mPGES-1 while maintaining prostacyclin synthase activity.
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DOI：
10.4155/fmc-2021-0056
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发表时间：
2021-06
影响因子：
4.2
通讯作者：
Diana T Ruan;N. Tang;Hironori Akasaka;Renzhong Lu;K. Ruan
中科院分区：
文献类型：
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作者：
Diana T Ruan;N. Tang;Hironori Akasaka;Renzhong Lu;K. Ruan
目的：本研究调查了我们的酶联物，考克斯-2-10aa-mPGES-1和考克斯-2-10aa-PGIS，作为细胞交叉筛选靶标，用于快速鉴定抑制炎性PGE 2生物合成同时维持前列环素合成的先导化合物。方法：我们整合虚拟和湿交叉筛选使用酶链快速识别先导化合物从一个大的化合物库。结果如下：从380，000种化合物中，实际上用酶链交叉筛选，鉴定了1576种化合物，并使用过表达单个酶链的HEK 293细胞作为靶标用于湿交叉筛选。鉴定了抑制mPGES-1活性的前15种先导化合物。获得了单独特异性抑制炎性PGE 2生物合成而不影响与PGI 2合成酶（PGIS）偶联的用于PGI 2生物合成的考克斯-2的顶级化合物。结论：酶链技术可以在很大程度上促进环氧合酶通路靶向药物的发现。
Aim: 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 PGE2 biosynthesis while maintaining prostacyclin synthesis. Methods: We integrated virtual and wet cross-screening using Enzymelinks to rapidly identify lead compounds from a large compound library. Results: 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 PGE2 biosynthesis alone without affecting COX-2 coupled to PGI2 synthase (PGIS) for PGI2 biosynthesis was obtained. Conclusion: Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.