Servier Drug Discovery Program
Molecular and Translational Drug Discovery
G protein-coupled receptors (GPCRs) are the largest family of receptors and are responsible for regulating a range of physiological functions and pathology. Given the broad range of processes in which these receptors are implicated, it is unsurprising that approximately 30% of marketed drugs target this receptor family. We utilize a variety of platforms, techniques and collaborations in order to progress our GPCR discovery projects towards clinical development. Research in this laboratory covers a range of disciplines including molecular biology, molecular pharmacology, cellular & native tissue pharmacology and translational biology.
Servier Discovery Program: Our portfolio includes multiple GPCR projects at differing stages of the drug discovery process, ranging from target validation though to hit-to-lead chemistry. Our primary therapeutic areas of interest are schizophrenia and metabolic disorders.
Additional Projects: The lab has a strong research interest in disorders associated with the basal ganglia in the CNS, including projects studying the role of the orphan GPCRs in schizophrenia and cognitive disorders and the muscarinic M5 receptor in addiction.
To probe molecular mechanisms of action, we utilise a range of biochemical, pharmacological and cell-signalling assays including radioligand binding, TR-FRET, calcium mobilization, cAMP accumulation, GTPγ35S binding, ERK1/2, CREB and GSK3ß phosphorylation and label-free technology (xCELLigence). Additionally we develop and run cellular assays in 384-well format to enable high-throughput and primary SAR screening as well as evaluation of biased agonism.
Figure legend: Positive (top) and negative (bottom) allosteric modulation of acetylcholine (ACh)-stimulated inositol phosphate accumulation in CHO cells expressing the muscarinic M5 receptor after treatment with the receptor alkylating agent, phenoxybenzamine (PBZ). Adapted from Berizzi et al. (2016) Mol Pharmacol. 90(4):427-36.
Cellular and native pharmacology
To better reflect the in vivo situation, we study GPCR pharmacology (using many of the assays above) in native tissue and cellular systems, including isolated brain tissue, primary cultured neurons, isolated primary blood cells and immortalized cell lines endogenously expressing GPCR targets.
Figure legend: Variation in chemotactic response in peripheral blood mononuclear cells (PBMCs) and a monocyte-like cell lines (THP-1) with a range of chemoattractants.
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 electrophysiology, in vivo neurobiology, cognition and metabolism models and PK-PD-receptor occupancy studies, often in collaboration with the Centre for Drug Candidate Optimisation at MIPS.
- Dr Catherine Rochat, Alliance Management
- Dr Jean-Philippe Stephan and Dr Celine Legros , Biotechnology
- Dr Elizabeth Harley & Dr Philippe Delerive, Metabolism Innovation Pole
- Dr Mark Millan, Dr Elisabeth Mocaer and Dr Clotilde Mannoury la Cour, CNS Innovation Pole
- Dr Philippe Pastoureau & Dr Massimo Sabatini, Immuno-inflammation Innovation Pole
- Dr Anne-Marie Chollet, Dr Arnaud Le Tiran and Dr Philippe Gloanec, Medicinal Chemistry
Monash Institute of Pharmaceutical Sciences
- Professor Arthur Christopoulos, Drug Discovery Biology
- Professor Patrick Sexton, Drug Discovery Biology
- Professor Roger Summers, Drug Discovery Biology
- Professor Jonathan Baell, Medicinal Chemistry
- Dr David Shackleford, Centre for Drug Candidate Optimisation
- Professor David Spanswick, Biomedicine Discovery Institute, Monash University
- Professor Michael Cowley and Dr Stephanie Simmonds, Biomedicine Discovery Institute, Monash University
- Professor Andrew Lawrence, Florey Institute of Neuroscience and Mental Health
- Dr Jess Nithianantharajah, Florey Institute of Neuroscience and Mental Health
Diepenhorst NA, Nowell CJ, Rueda P, Henriksen K, Pierce T, Cook AE, Pastoureau P, Sabatini M, Charman WN, Christopoulos A, Summers RJ, Sexton PM, Langmead CJ. High throughput quantitative analysis of human osteoclast differentiation and activity. Anal Biochem. 2017, 519:51-56.
Riddy DM, Cook AE, Diepenhorst NA, Bosnyak S, Brady R, Mannoury la Cour C, Mocaer E, Summers RJ, Charman WN, Sexton PM, Christopoulos A, Langmead CJ. Isoform-specific biased agonism of histamine H3 receptor agonists. Mol Pharmacol. 2017, 91(2):87-99. Erratum in: Mol Pharmacol. 2017, 91(3):263.
Choy KH, Shackleford DM, Malone DT, Mistry SN, Patil RT, Scammells PJ, Langmead CJ, Pantelis C, Sexton PM, Lane JR, Christopoulos A. Positive allosteric modulation of the muscarinic M1 receptor improves efficacy of antipsychotics in mouse glutamatergic deficit models of behavior. J Pharmacol Exp Ther. 2016, 359(2):354-365.
Berizzi A, Gentry PR, Rueda P, den Hoedt S, Sexton PM, Langmead CJ, Christopoulos A. Molecular mechanisms of action of M5 muscarinic acetylcholine receptor allosteric modulators. Mol Pharmacol. 2016, 90(4):427-36
Rueda P, Harley E, Lu Y, Stewart GD, Fabb S, Diepenhorst NA, Cremers B, Rouillon M-H, Wehrle I, Geant A, Lamarche G, Leach K, Charman WN, Christopoulos A, Summers RJ, Sexton PM, Langmead CJ. Murine GPRC6A mediates cellular responses to L-amino acids, but not osteocalcin variants. PLoS ONE. 2016. e0146846.
Riddy DM, Valant C, Rueda P, Charman WN, Sexton PM, Summer RJ, Christopoulos A, Langmead CJ. Label-free kinetics: exploiting functional hemi-equilibrium to derive rate constants for muscarinic receptor antagonists. Mol Pharmacol. 2015, 88:779-90
Christopoulos A, Changeux J-P, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, Pin J-P, Sexton PM, Kenakin TP, Ehlert FJ, Spedding M, Langmead CJ. International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev. 2014; 66:918-47
Langmead CJ, Christopoulos, A. Functional and structural perspectives on allosteric modulation of GPCRs. Curr. Opin. Cell Biol. 2014; 27, 94-101.
Langmead CJ, Christopoulos A. Supra-physiological efficacy at GPCRs: superstition or super agonists? Br J Pharmacol. 2013; 169:353-356
Langmead CJ, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther. 2008; 117(2):232-43.
Langmead CJ & Christopoloulos A. Allosteric agonists of 7TM receptors: Expanding the pharmacological toolbox. Trends Pharmacol Sci. 2006; 27(9): 475-81.
Dr Patricia Rueda
Research Fellow and Project Lead
Research Fellow and Project Lead
Dr Greg Stewart
Research Fellow and Project Lead
Dr Sanja Bosnyak-Gladovic
Dr Rocio De La Fuente
Dr Natalie Diepenhorst
Dr Stewart Fabb
Dr Monica Langiu
Dr Cherry Mao
Dr Jon Merlin
Dr Tracie Pierce
Dr Mohsin Sarwar
Yao (Jackie) Lu
PhD Student (with Professor Christopulos)
- Servier and NHMRC