CHED 1320 |
| The ion transport activity of the sarco/endoplasmic reticulum calcium ATPase (SERCA) is specifically and potently inhibited by the small molecule 2,5-di-tert-butyl-hydroquinone (BHQ). We have investigated the relative importance of the nature and position of BHQ's four substituents for enzyme inhibition by employing a combination of organic synthesis, bioassays, and computational docking. The inhibitory potencies of both synthesized and commercially available BHQ derivatives were determined in ATPase activity assays. Whereas only one hydroxyl group was necessary for effective SERCA inhibition, both alkyl groups were required. Maximum inhibitory potency was observed in compounds with two hydroxyl and two alkyl groups comprised of four or five carbon atoms each. The inhibition assays were complemented by computational docking of BHQ analogues into the crystal structure of SERCA in the E2 conformation using the program GOLD in conjunction with the ChemScore scoring function. The obtained consensus orientations showed that inhibitor binding to SERCA was primarily mediated by one hydrogen bond and hydrophobic interactions involving the inhibitors' hydroxyl and alkyl side groups, respectively. The docking scores allowed a distinction between active and inactive compounds, which is a crucial requirement for the virtual screening of large compound databases for novel SERCA inhibitors in the future. |
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Undergraduate Research Poster Session: Medicinal
2:00 PM-4:00 PM, Monday, March 26, 2007 Hyatt Regency Chicago -- Riverside Center, Poster
Division of Chemical Education |