Diana T Ruan1, Nanhong Tang2,3, Hironari Akasaka2, Renzhong Lu2, Ke-He Ruan2. 1. Columbia University Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, USA. 2. The Center for Experimental Therapeutics & Pharmacoinformatics, Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA. 3. Visiting Scholar from Department of Hepatobiliary Surgery & Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China.
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.
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.
Authors: Masako Nakanishi; David C Montrose; Patsy Clark; Prashant R Nambiar; Glenn S Belinsky; Kevin P Claffey; Daigen Xu; Daniel W Rosenberg Journal: Cancer Res Date: 2008-05-01 Impact factor: 12.701
Authors: Birgit Waltenberger; Katja Wiechmann; Julia Bauer; Patrick Markt; Stefan M Noha; Gerhard Wolber; Judith M Rollinger; Oliver Werz; Daniela Schuster; Hermann Stuppner Journal: J Med Chem Date: 2011-04-20 Impact factor: 7.446