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Computer-Aided Selective Optimization of Side Activities of Talinolol

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journal contribution
posted on 29.05.2019, 00:00 by Kerstin Hiesinger, Jan S. Kramer, Janosch Achenbach, Daniel Moser, Julia Weber, Sandra K. Wittmann, Christophe Morisseau, Carlo Angioni, Gerd Geisslinger, Astrid S. Kahnt, Astrid Kaiser, Anna Proschak, Dieter Steinhilber, Denys Pogoryelov, Karen Wagner, Bruce D. Hammock, Ewgenij Proschak
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.