Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1091-1103 |
Number of pages | 13 |
Journal | Future Medicinal Chemistry |
Volume | 13 |
Issue number | 13 |
DOIs | |
State | Published - Jul 2021 |
Externally published | Yes |
Keywords
- COX-2
- cyclooxygenase-2
- Enzymelink
- inhibitors
- microsomal prostaglandin Esynthase-1
- mPGES-1
- PGIS
- prostacyclin synthase
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology
- Drug Discovery