%0 Journal Article %1 Xing2011sEHSBVS %A Xing, Li %A McDonald, Joseph J. %A Kolodziej, Steve A. %A Kurumbail, Ravi G. %A Williams, Jennifer M. %A Warren, Chad J. %A O’Neal, Janet M. %A Skepner, Jill E. %A Roberds, Steven L. %D 2011 %J Journal of Medicinal Chemistry %K drug-design sEH soluble-epoxide-hydrolase structure-based-virtual-screening virtual-screening %N 5 %P 1211-1222 %R 10.1021/jm101382t %T Discovery of Potent Inhibitors of Soluble Epoxide Hydrolase by Combinatorial Library Design and Structure-Based Virtual Screening %U http://dx.doi.org/10.1021/jm101382t %V 54 %X Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90\% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC50 determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

@article{Xing2011sEHSBVS, abstract = { Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90\% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC50 determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents. }, added-at = {2017-02-14T00:26:05.000+0100}, author = {Xing, Li and McDonald, Joseph J. and Kolodziej, Steve A. and Kurumbail, Ravi G. and Williams, Jennifer M. and Warren, Chad J. and O’Neal, Janet M. and Skepner, Jill E. and Roberds, Steven L.}, biburl = {https://www.bibsonomy.org/bibtex/28379bcfc69419820e903050251ecdb4f/salotz}, description = {Discovery of Potent Inhibitors of Soluble Epoxide Hydrolase by Combinatorial Library Design and Structure-Based Virtual Screening - Journal of Medicinal Chemistry (ACS Publications)}, doi = {10.1021/jm101382t}, eprint = {http://dx.doi.org/10.1021/jm101382t}, interhash = {5f0171abf6a6f6952d8678c034b4309c}, intrahash = {8379bcfc69419820e903050251ecdb4f}, journal = {Journal of Medicinal Chemistry}, keywords = {drug-design sEH soluble-epoxide-hydrolase structure-based-virtual-screening virtual-screening}, note = {PMID: 21302953}, number = 5, pages = {1211-1222}, timestamp = {2017-02-14T00:26:05.000+0100}, title = {Discovery of Potent Inhibitors of Soluble Epoxide Hydrolase by Combinatorial Library Design and Structure-Based Virtual Screening}, url = {http://dx.doi.org/10.1021/jm101382t}, volume = 54, year = 2011 }