Figure 1. Modeling of GPR68 in a conformation
competent to recognize lorazepam, a hit from an
empirical screen. Against the modeled structure 3
million compounds were docked screen, revealing
ogerin, a PAM specific for GPR68 and active in vivo.
Figure 2. The novel agonist PZM21 docked into
the μ-opioid receptor.
G Protein Coupled Receptors (GPCRs) are the largest
family of signaling proteins in the genome, sitting atop
hundreds of transduction cascades that determine how cells
and tissues respond to stimuli and to environmental cues.
This, their direct accessibility to molecules outside the
cell, and their great ligand binding sites, have made them
the protein family most targeted by drugs.
The structural renaissance begun by the determination of the
β2-adrenergic receptor has made ever-more of these receptors
accessible to structure-based discovery. In
proof-of-concept docking campaigns vs the β2, the A2a, D3,
CXCR4, and muscarinic receptors, we observed hit rates
ranging from 17% to over 50% (active hits/number
experimentally tested), with potencies ranging from
sub-nanomolar to low micromolar.
Bolstered by these results, we are seeking novel GPCR
ligands that confer new biology. Three projects are being
1. With Bryan Roth’s group, we are deorphanizing
the 120 orphan GPCRs in the genome. Combining empirical
screening, modeling, and docking, specific probe molecules
have emerged for three orphan GPCRs, including for GPR68,
where the new probe (ogerin), a direct docking hit, was used
to show that GPR68 was involved in fear-based learning in
the mouse (Huang, 2015).
2. With the Sunahara, Kobilka, and Gmeiner labs we
seek new allosteric molecules for GPCRs. Allosteric
molecules have great signaling advantages, modulating the
activities of primary transmitters without themselves
3. With the Roth, Gmeiner & Kobilka labs, we are
seeking novel ligands for orthosteric sites for well-studied
targets. Even against such sites, new chemotypes can confer
new signaling properties, preferentially activating one GPCR
effector over another. For instance, in the μ-opioid
receptor, docking revealed a novel agonist that activated G
protein signaling without activating arrestin signaling. In
a mouse model, this new agonist (PZM21) conferred analgesia
without respiratory depression and with reduced reinforcing
behavior. As well as leading us into cool new biology in
several areas, this project has become a testing ground for
our latest docking and chemoinformatics methods.
Recent papers include:
- A Manglik, H Lin, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature (2016).
- XP Haung, J. Karpiak, et al. Allosteric ligands for the pharmacologically dark receptors GPR68 & GPR65. Nature 527, 477-83 (2015).
- DR Weiss et al., Conformation guides molecular efficacy in docking screens of activated %beta;-2 adrenergic G protein coupled receptor. ACS Chem Biol 8, 1018-26 (2013).
- J. Carlsson, RG Coleman, et al. Comparing Structure-based Ligand Discovery from a Homology Model and the Crystal Structure of the Dopamine D3 Receptor. Nature Chem. Biol. 7, 769-778 (2011).
Supported by NIH U01104974, GM106990 and GM59957.