Open AccessEngineering ‘Enzymelink’ for screening lead compounds to inhibit mPGES-1 while maintaining prostacyclin synthase activity
Author(s) -
DiYun Ruan,
Nanhong Tang,
Hironari Akasaka,
Renzhong Lu
Publication year - 2021
Publication title -
future medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.708
H-Index - 69
eISSN - 1756-8927
pISSN - 1756-8919
DOI - 10.4155/fmc-2021-0056
Subject(s) - prostacyclin , biosynthesis , cyclooxygenase , virtual screening , chemistry , lead compound , atp synthase , drug discovery , high throughput screening , pharmacology , biochemistry , enzyme , biology , in vitro
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 PGE 2 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 PGE 2 biosynthesis alone without affecting COX-2 coupled to PGI 2 synthase (PGIS) for PGI 2 biosynthesis was obtained. Conclusion: Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.