In the past decade, GPCR drug discovery has been transformed by the rapidly growing availability of 3D structures and a better understanding of atomistic mechanisms of signaling. This has been especially notable for the key receptors in pain and addiction disorders, including opioid and cannabinoid families, where all receptors have been structurally characterized in both inactive and active states.  This talk will describe how these structures and new structure-based computational approaches enable discovery of new GPCR ligands and lead series with improved functional and safety profiles for pain and addiction disorders.  

The first technology, V-SYNTHES, enables rapid identification of novel chemotypes for GPCR hits and leads in Giga-scale REadily AvaiLable (REAL) libraries of drug-like compounds (Sadybekov et al Nature, 601, 452-459)  This iterative synthon-based virtual screening technology has been validated by the prospective discovery of novel antagonists for Cannabinoid (CB) from the 11 Billion compounds of REAL Space. Chemical synthesis and experimental testing of 60 compounds predicted by V-SYNTHES identified 14 novel sub-micromolar antagonists. Optimization of the best lead series by a simple SAR-by-catalog screen in the same REAL Space identified CB2 selective antagonists with nanomolar potency and 200-fold CB2/CB1 selectivity. The approach also shows promising results for other GPCRs and other classes of therapeutic targets.    The next generation, fully automated V-SYNTHES2.0 is being also developed to include rapidly growing REAL Space (currently 29 Billion compounds), potentially expanding to Tera-Scale (10¹²-10¹⁵ compounds) screening in the next few years.

A synergistic rational design approach employs structure-guided bitopic derivatization of existing high-affinity ligand scaffolds to design new functional properties. In one example, the approach was used to discover bitopic ligands targeting both orthosteric pockets and the allosteric sodium ion binding pocket in Class A GPCRs. Because this highly conserved site deep in the 7TM helical bundle is a key part of the Class A GPCR activation mechanism, the bitopic ligands acquire new functional properties. In the application of this approach to opioid receptors, we show that the bitopic extension can differentially modulate signaling towards specific functional pathways, involving distinct G-protein subtypes. Moreover, the functionally selective fentanyl-based design demonstrated effective analgesia without respiratory depression and other opioid side effects (Faouzi et al.  (2022) In revision), while the approach is being tested on other receptors.   Further examples of rational scaffold functionalization, including