Drug Discovery |
The specific focus of the Orphan Receptor Laboratory is the discovery of new drugs for receptors where the partner hormone is still to be found. These are called ‘orphan’ G protein-coupled receptors and make up the majority of all receptors in the family. The team combines high throughput GPCR signalling assays with sophisticated computational approaches to understand the molecular pharmacology of understudied receptors, particularly in cardiovascular research. Specific techniques commonly used in the Orphan Receptor Laboratory include site-directed mutagenesis, epitope tagging and monitoring of GPCR expression and cellular localisation, biosensor-based cAMP, calcium and ERK1/2 activation, NanoBiT G protein and arrestin assays, and reporter gene assays. More recently, the laboratory has moved to the use of fluorescent ligands in the place of radioligands and has added human lung organoids to their repertoire of physiologically-relevant culture systems.
Current projects
Current projects in the lab are focused on understanding the molecular pharmacology of poorly understood orphan GPCRs that have been implicated in various aspects of cardiovascular disease or cancer.
If you are interested in exploring the possibility of Honours or PhD studies with the Orphan Receptor Laboratory, please contact A/Prof Nicola J Smith.
Highlighted publications
- Smith, N.J.* & Murray, F. (2024) Shifting our perspective on orphan G protein-coupled receptors. Nature Structural & Molecular Biology. 31:582-583
- Stavrou, M.R., So, S.S., Finch, A.M., Ballouz, S. & Smith, N.J.* (2023), Gene expression analyses of TAS1R taste receptors relevant to the treatment of cardiometabolic disease. Chemical Senses, vol. 48 Â
- Ngo, T.*, Wilkins, B.P.*, So, S.S.*, Keov, P., Chahal, K.K., Finch, A.M., Coleman, J.L.J., Kufareva, I**, Smith, N.J.**.(2021) Matters Arising: Orphan G protein-coupled receptor, GPR37L1: pharmacological toolbox empty once again. Nature Chemical Biology, 17:383-386.
- Coleman, J.L.J.*, Ngo, T.*, Smythe, R.E., Cleave, A.J., Jones, N.M., Graham, R.M., Smith, N.J.** (2020) The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases. Scientific Reports. 10, 19995 (2020)
- Ngo, T., Kufareva, I., Coleman, J.L., Graham, R.M., Abagyan, R., Smith, N.J.* (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. British Journal of Pharmacology, 173(20):2934-2951.
Our experts
Associate Professor Nicola Smith - Group Leader
Dr Nicola J. Smith is an Associate Professor and Head of the Department of Pharmacology, School of Biomedical Sciences at ÁñÁ«¹ÙÍø Sydney. She is a molecular pharmacologist with internationally recognised expertise in the area of orphan G protein-coupled receptors (GPCRs), where she has gained a reputation for the rigorous examination of ligand:receptor pairings and for exploring the therapeutic potential of orphan GPCRs using cellular and animal models of disease.
A/Prof Smith received her PhD from The University of Melbourne (2007), which she completed at the Baker Heart Research Institute (2007) where she investigated the role of GPCRs in cardiac hypertrophy. She was awarded a prestigious National Health & Medical Research Council CJ Martin/National Heart Foundation Overseas Fellowship (top ranked applicant) to then train in molecular pharmacology at The University of Glasgow (2007-2011) before returning to Australia to a position at the Victor Chang Cardiac Research Institute. A/Prof Smith established her independent research group in 2016 with the help of a National Heart Foundation Future Leader Fellowship (Level 2) and moved to ÁñÁ«¹ÙÍø Sydney to start the Orphan Research Laboratory in mid-2019. During her career, she has been awarded >$2.5 million in research and fellowship funding from the NHMRC and National Heart Foundation and received national and international accolades including Young Tall Poppy and Young Investigator Awards. A/Prof Smith is currently the Scientific Advisor Chair of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, where she actively engages in promoting the importance of pharmacology and early career researchers to human health and disease.
Team members
- Brendan Wilkins
- Kinjal Patel
- Mariah Stavrou
- Heijie (Jack) Zhang
- Ishika Jaitly
Associated academics
- , Skaggs School of Pharmacy & Pharmaceutical Sciences, UCSD, CA, USA
- , University of Technology Sydney
- Associate Professor Luke Hunter, School of Chemistry, ÁñÁ«¹ÙÍø Sydney
- , Department of Molecular Medicine, SBMS, ÁñÁ«¹ÙÍø Sydney
- Dr Shafagh Waters, Scientia Fellow, Department of Pharmacology, SBMS, ÁñÁ«¹ÙÍø Sydney
- Dr John Lock, Scientia Fellow, Department of Pharmacology, SBMS, ÁñÁ«¹ÙÍø Sydney
- Dr Angela Finch, Department of Pharmacology, SBMS, ÁñÁ«¹ÙÍø Sydney
- Dr Felicity Davis & Dr Valentina Rodriguez Paris, Department of Molecular Medicine, SBMS, ÁñÁ«¹ÙÍø Sydney
- , Department of Molecular Medicine, SBMS, ÁñÁ«¹ÙÍø Sydney
- , Victor Chang Cardiac Research Institute, Sydney
- , Victor Chang Cardiac Research Institute, Sydney
- , Newborn Care Centre, Royal Hospital for Women, Randwick, Sydney
- , QIMR Berghofer Medical Research Institute, Queensland
- Dr Sara Ballouz, School of Computer Science and Engineering, ÁñÁ«¹ÙÍø Sydney
Honor students
- Zoe Eastwood
- Haoyi Han
- Ian Reininger-Chatzigiannakis
- Paige Pfeiffer
Research Theme