Chemistry of Biology Lecture: “A Cure for Pain: Structure-based Probe Discovery for GPCRs”

Seminar series
Organic Colloquium
Tue, Apr 26 2:00pm
Cram Conference Room – 3440 Molecular Sciences Bldg
Speaker Professor Brian K. Shoichet
University of California, San Francisco
Department of Pharmaceutical Chemistry

Special CHEM C105/CM205A: Chemistry of Biology Lecture


Chemistry-Biology Interface Lecture

“A Cure for Pain: Structure-based Probe Discovery for GPCRs”

Abstract.  If structure-based drug design has only occasionally lived up to the expectations of its boosters, one area where the technique has reliably contributed has been the discovery of unanticipated chemotypes.  These new chemotypes are often accompanied by new pharmacology.  Two places where such new ligands are urgently needed are against orphan receptors, and against therapeutic targets where established ligands are burdened by therapeutic liabilities.

              Working with the lab of Bryan Roth, a small library of privileged molecules was physically screened against a subset of the 200 orphan and understudied GPCRs in the genome.  Among the hits was the benzodiazepine lorazepam, which acted as positive allosteric modulator of the orphan receptor GPR68.  We used lorazepam to template GPR68 modeling, and used the structure that emerged in a docking screen of 3 million molecules.   High-scoring molecules were tested against GPR68, and a cycle of optimization ultimately led to a molecule with about 100-fold higher efficacy as a PAM of GPR68, with against most other CNS targets.  This probe was used to test the role in of GPR68 in hippocampul behavior associated with the hippocampus, where the receptor is most highly expressed, using WT and GPR68-knockout mice.  A role for GPR68 in fear-based learning emerged.

              Working with the labs of Brian Kobilka, Bryan Roth and Peter Gmeiner, a docking screen was undertaken against the Mu Opioid Receptor (MOR).  Unlike GPR68, ligand precedence here is enormous, and we sought unexplored chemotypes that might have new signaling properties.  Hits from the docking screen revealed agonists with new scaffolds but only micromolar affinities.  However, two rounds of structure-based optimization resulted in a lead with a 4 nM EC50.  This molecule was specific for the MOR over the Kappa, Delta, and Noceciptin sub-types, and was biased toward Gi over arrestin signaling.  As it is the latter that is associated with the dose-limiting toxicities of the classic opioid drugs, we tested this new probe for analgesia and for stereotypic opioid toxicities in a mouse model, with intriguing results. Opportunities for structure-based chemotype discovery against the GPCRome will be considered.