Thorsten Nowak
C4X Discovery
Manchester
United Kingdom
Title: Discovery of Novel Orexin-1 Selective Antagonists using NMR Guided Conformational Design
Biography
Biography: Thorsten Nowak
Abstract
Orexin-1 and Orexin-2 are Class A GPCRs primarily found in the hypothalamus and locus coeruleus. These receptors have been linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuroendocrine function, and regulation of the sleep−wake cycle. Importantly they are also associated with dopaminergic neurons of the ventral tegmental area (VTA) that are critical elements of the reward system. The presentation will detail the impact of a new NMR-enabled conformational design approach1on the identification and optimization of novel highly selective Orexin-1 antagonists which show significant in vivo activity. Moreover, it will be described how the detailed understanding of the experimentally determined conformational behavior of small molecule ligands when coupled with GPCR homology modeling and targeted mutagenesis (HGMP) provide novel insights into the likely pharmacophore as well as the origin of the exquisite selectivity of the described Orexin-1 antagonists.The HGMP method has been developed by Evotec in conjunction with the Oxford University to support GPCR structure-based drug discovery programs.