Abstract

GPCR Structure-Based Drug Discovery: Identification and Structural Insights into Selective and Non-selective Orexin-1 & 2 Antagonists for the Treatment of Insomnia and Addiction Disorders

Ben Tehan, Senior Computational Chemist, Heptares Therapeutics

G-protein coupled receptors (GPCRs) play a crucial role in many diseases and are the site of action of a large percentage of current drugs. Despite this rich history many opportunities remain for clinical intervention, as successful NCEs have not been developed for several validated GPCR targets, and there is a scarcity of high quality molecules for difficult sub-families including metabotropic glutamate, chemokine and neuropeptide receptors.
Instability of GPCRs when removed from their cell membrane environment has severely limited the application of structure-based and fragment-based drug discovery techniques to the target class. The Heptares approach to GPCR drug discovery nucleates around a unique ability, using stabilised receptor (StaR®) technology, to mutationally stabilise receptors in precisely defined biologically-relevant conformations. The platform is used to design efficient small-molecules, with a focus on structure-based approaches to problematic targets. StaRs® are amenable to techniques that cannot be readily used with wild-type GPCRs, including fragment screening, biophysical kinetic profiling and crystallographic studies.
The orexins are two neuropeptides produced in the hypothalamus which bind to orexin-1 (OX1) and orexin-2 (OX2) GPCRs. Antagonism of the orexin receptors has potential utility in numerous areas including insomnia, migraine, addiction and panic. OX1 and OX2 StaRs® have been generated and have facilitated rapid progression of a dual orexin receptor antagonist (DORA) series to a pre-clinical candidate. Structural insights into the DORA series along with the structural basis for differing Orexin antagonists’ selectivity will be presented, as will the use of information from several distinct chemotypes in the structure-based design of an advanced series of OX1 antagonists.