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Computer-Aided Selective Optimization of Side Activities of Talinolol
- Hiesinger, Kerstin;
- Kramer, Jan S;
- Achenbach, Janosch;
- Moser, Daniel;
- Weber, Julia;
- Wittmann, Sandra K;
- Morisseau, Christophe;
- Angioni, Carlo;
- Geisslinger, Gerd;
- Kahnt, Astrid S;
- Kaiser, Astrid;
- Proschak, Anna;
- Steinhilber, Dieter;
- Pogoryelov, Denys;
- Wagner, Karen;
- Hammock, Bruce D;
- Proschak, Ewgenij
- et al.
Published Web Location
https://doi.org/10.1021/acsmedchemlett.9b00075Abstract
Selective optimization of side activities is a valuable source of novel lead structures in drug discovery. In this study, a computer-aided approach was used to deorphanize the pleiotropic cholesterol-lowering effects of the beta-blocker talinolol, which result from the inhibition of the enzyme soluble epoxide hydrolase (sEH). X-ray structure analysis of the sEH in complex with talinolol enables a straightforward optimization of inhibitory potency. The resulting lead structure exhibited in vivo activity in a rat model of diabetic neuropatic pain.
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