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Molecular & Translational Drug Discovery

Structural Biology

In collaboration with Patrick Sexton and Denise Wootten we use high-resolution, single-particle cryo-EM to enable structure-guided drug discovery for a range of GPCR targets.

cryo-EM workflow

Single-particle cryo-EM workflow for high resolution structure-guided drug discovery

Molecular and Cellular Pharmacology

To probe molecular mechanisms of action, we utilise a range of biochemical, pharmacological and cell-signalling assays including radioligand binding, TR-FRET, calcium mobilisation, cAMP accumulation, GTPγ35S binding, ERK1/2 phosphorylation and label-free technology.  Additionally, we develop and run cellular assays in 384-well plate format to enable high-throughput and primary SAR screening.

Histamine H3 antagonists

Kinetic and selectivity differentiation of histamine H3 receptor antagonists. Adapted from Riddy et al., (2019) Neuropharmacology (doi:10.1016/j.neuropharm.2018.10.028)

Native and Human Tissue Pharmacology

To better reflect the in vivo situation, we study GPCR expression and pharmacology (using many of the assays above) in native tissue and cellular systems, including isolated human and rodent brain tissue, primary cultured neurons, and isolated primary blood cells.

GPR52 neurons

Expression profiling of the orphan receptor, Gpr52 (white), in the dorsal striatum (DS) of mouse brain using RNAscope fluorescent in situ hybridisation. Gpr52 is primarily co-expressed with the dopamine D2 receptor (Drd2; red), but not the dopamine D1 receptor (Drd1; green), in medium spiny neurons (adapted from Spark et al., 2020 [doi.org/10.1021/acschemneuro.0c00197]).


Atherosclerotic plaque

Atherosclerotic plaque from the aorta of a wild-type mouse fed a 60% high fat diet for 20 weeks, as imaged using Coherent Anti-Stokes Raman Scattering (CARS) microscopy (white = macrophages / lipids; green = collagen; Sanja Bosnyak-Gladovic & Cameron Nowell).


Translational Biology


To provide translation from recombinant and cellular studies to in vivo models and better understand drug mechanism of action, we utilise a range of translational approaches, including in vivo neurobiology, obesity and metabolism models, and patient-derived blood samples.

touchscreen

Phenotype of wild-type and orphan GPCR knockout mice in the object-location paired associates learning (PAL) touchscreen task (Stewart et al., 2020 [unpublished observations]).

M5 NAM

Microinjection of the muscarinic M5 receptor negative allosteric modulator (NAM), ML375, in the dorsolateral, but nor dorsomedial striatum of alcohol-experienced iP rats reduces alcohol self-administration (adapted from Berizzi et al., (2018) Neuropsychopharmacology; doi 10.1038/s41386-017-0007-3).

For further information, please contact Chris Langmead.