Xing_2011_J.Med.Chem_54_1211

Reference

Title : Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening - Xing_2011_J.Med.Chem_54_1211
Author(s) : Xing L , McDonald JJ , Kolodziej SA , Kurumbail RG , Williams JM , Warren CJ , O'Neal JM , Skepner JE , Roberds SL
Ref : Journal of Medicinal Chemistry , 54 :1211 , 2011
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 IC(50) 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.

PubMedSearch : Xing_2011_J.Med.Chem_54_1211
PubMedID: 21302953
Gene_locus related to this paper: human-EPHX2

Related information

Inhibitor CHEMBL1689794
Gene_locus human-EPHX2
Structure 3PDC

Citations formats

Xing L, McDonald JJ, Kolodziej SA, Kurumbail RG, Williams JM, Warren CJ, O'Neal JM, Skepner JE, Roberds SL (2011)
Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening
Journal of Medicinal Chemistry 54 :1211

Xing L, McDonald JJ, Kolodziej SA, Kurumbail RG, Williams JM, Warren CJ, O'Neal JM, Skepner JE, Roberds SL (2011)
Journal of Medicinal Chemistry 54 :1211