Drug Discovery Innovation Group
G protein-coupled receptors (GPCRs) are vital for all cells to detect their external environment and communicate with other cells. They play a role in virtually every aspect of human physiology. GPCR signalling pathways are often corrupted in disease, making GPCRs a major target for drug development and the most accessible targets for FDA-approved medications. Despite this, drug discovery efforts for most GPCRs have been unsuccessful, even though many are strongly associated with various illnesses.
Our research is focused on revealing the molecular mechanisms underlying GPCR function through structural biology, protein engineering, biochemistry, molecular pharmacology and both small molecule and antibody discovery. Our overarching goal is to develop innovative strategies that facilitate the development of next-generation therapeutics targeting GPCRs.
About our research
Human cells sense their environment through GPCRs, the targets for 30% of approved drugs. Most GPCRs, however, remain un-targeted, many approved GPCR drugs are sub-optimal, and new GPCR drug approvals have stalled, reflecting the challenge of GPCR drug discovery. The inability to develop selective GPCR-targeting drugs has hindered the exploitation of most of these receptors to treat many diseases. In general, humans express families of GPCRs (e.g. 36 monoamine GPCRs) that sense and respond to the same or similar endogenous ligands (e.g. dopamine/serotonin), and thus have virtually identical ligand binding sites but modulate different physiological responses. The structural similarity of GPCR family members makes receptor-specific, small molecule drug development challenging, leading to approved drugs with many off-target adverse effects. Furthering our understanding of the molecular mechanism, or structural basis of ligand induced GPCR activation will ultimately increase the chances of developing safer medicines. Molecular research of GPCRs is challenging because samples of these proteins are laborious and expensive to produce. The laboratory develops novel technology and processes that enable the production of GPCR samples for molecular research and for next-generation drug discovery.
- G protein-coupled receptors (GPCRs)
- Drug discovery
- Antibodies and nanobodies
- Cell signalling
G protein-coupled receptors
G protein-coupled receptors (GPCRs) are the largest family of membrane proteins encoded by the human genome, and are vital for nearly all forms of life. GPCRs are located on the cell surface and allow cellular communication by transmitting extracellular stimulus into intracellular signals, this includes responding to external signals such as hormones, light, neurotransmitters, peptides etc. GPCRs are located on the cell surface and are responsible for detecting and responding to various external signals such as hormones, light, and neurotransmitters. Upon receiving these signals, GPCRs activate an intracellular signal transduction pathway, leading to a cellular response. This is why GPCRs are so important: they are the gatekeepers that allow our bodies to respond to the environment and function properly. Consequently, GPCRs play major roles in almost all aspects of human physiology and are therefore implicated in a variety of disease states. Our lab is focused in using multi-disciplinary approaches (including protein engineering, molecular pharmacology, and structural biology) to unravel important details about the molecular mechanisms underlying the action of GPCRs, and develop improved approaches for drugging these important therapeutic targets.
Nanobodies (Nbs) are small single-domain proteins that are only 1/10th the size of regular antibodies (IgGs), and are derived from heavy-chain only antibodies of found natively in camelids (camels/llamas/alpacas). Due to their small size, high stability, adaptability and ease of expression, nanobodies have become invaluable tools of scientific research for probing the function of a wide range of proteins. Further, there is immense interest in the use of nanobodies as potential therapeutic modalities particularly in diseases such as cancer and autoimmune disorders, with the first FDA-approved nanobody reaching the market in 2019. Our lab has developed novel approaches to help accelerate the identification of nanobodies against a variety of important biological targets.
Protein engineering and directed evolution
Protein engineering is the process of designing or modifying proteins to create new or improved functionalities. This can involve altering the amino acid sequence, structure, or other properties of the protein to improve its activity, stability, or specificity.
Directed evolution is a protein engineering technique that involves generating and screening a large number of randomly mutated proteins to identify variants with improved properties. This is achieved by introducing random mutations into the gene encoding the protein, expressing the mutant proteins in a host organism, and then screening the resulting proteins for the desired function.
Protein engineering and directed evolution are valuable tools for drug discovery because they allow the design or discovery of proteins with specific properties that can be used to facilitate drug discovery efforts. Our lab is interested in developing novel protein engineering solutions to tackle difficult problems with drug discovery efforts at integral membrane proteins, in particular GPCRs.
- Directed evolution
- Protein engineering
- Structural biology including NMR and Cryo-EM
- Molecular pharmacology
- Flow cytometry and FACS
- 3D printing
- Research commercialisation
- Andrew Zhang
- Yiling Yu
- Philipp Segeritz
- Kazem Asadollahi
- Herodion Hartono
- Renate Roeterink
- Jei Min Quah
- Saund Yadanar
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- Draper-Joyce, C.J., Khoshouei, M., Thal, D.M., Liang, Y.-L., Nguyen, A.T.N., Furness, S.G.B., Venugopal, H., Baltos, J.-A., Plitzko, J.M., Danev, R., Baumeister, W., May, L.T., Wootten, D., Sexton, P.M., Glukhova, A. and Christopoulos, A. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, [online] 558(7711), pp.559–563. doi:https://doi.org/10.1038/s41586-018-0236-6.
- Wu, F.-J., Williams, L.M., Abdul-Ridha, A., Gunatilaka, A., Vaid, T.M., Kocan, M., Whitehead, A.R., Griffin, M.D.W., Bathgate, R.A.D., Scott, D.J. and Gooley, P.R. (2020). Probing the correlation between ligand efficacy and conformational diversity at the α1A-adrenoreceptor reveals allosteric coupling of its microswitches. Journal of Biological Chemistry, [online] p.jbc.RA120.012842. doi:https://doi.org/10.1074/jbc.RA120.012842.