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Dr. GPCR Podcast

A Brief History of allosteric modulation with Dr. Arthur Christopoulos

About Dr. Arthur Christopoulos

"Arthur Christopoulos is the Professor of Analytical Pharmacology and the Dean of the Faculty of Pharmacy & Pharmaceutical Sciences, Monash University, Australia. His research focuses on novel paradigms of drug action at GPCRs, particularly allosteric modulation and biased agonism, and incorporates computational and mathematical modelling, structural and chemical biology, molecular and cellular pharmacology, medicinal chemistry, and preclinical models of behaviour and disease. His work has been applied to studies encompassing neurological and psychiatric disorders, cardiovascular disease, obesity, diabetes, chronic pain and addiction. He has received substantial, long-term support from international and national competitive, charitable and commercial sources, as well as being academic co-founder of three GPCR-focussed biotechnology companies.

Professor Christopoulos has over 360 publications, including in leading international journals such as Nature,Science and Cell, and has delivered over 180 invited presentations. He has served on the Editorial Board of 8 international journals and was a Councillor of the International Union of Basic and Clinical Pharmacology (IUPHAR). He has also been the recipient of multiple awards, including the John J. Abel Award and the Goodman and Gilman Award from the American Society for Pharmacology and Experimental Therapeutics; the Rand Medal from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists; the British Pharmacological Society’s Gaddum Memorial Award; the IUPHAR Sir James Black Analytical Pharmacology Lecturer; the GSK Award for Research Excellence and a Doctor of Laws (Honoris Causa) from the University of Athens. Since 2014, Clarivate Analytics have annually named him a Highly Cited Researcher in ‘Pharmacology & Toxicology’, and in 2021 also named him a Highly Cited Researcher in the additional category of ‘Biology & Biochemistry’. In 2017, he was elected a Fellow of the Australian Academy of Health and Medical Sciences, in 2018 as a Fellow of the British Pharmacological Society, and in 2021 he was elected a Fellow of the Australian Academy of Science for his seminal contributions to drug discovery. In 2023, he was elected a Fellow of the Pharmaceutical Society of Australia."

Dr. Arthur Christopoulos on the web


AI Summary

Quick recap

Yamina and Arthur discussed Arthur's career journey in pharmacology, including his mentors and significant discoveries related to allosteric receptors. They explored the evolution of the field, allosteric modulation concepts, and potential therapeutic approaches involving autoantibodies and allosteric modulators. Additionally, they covered the importance of target product profiles, reproducibility in experiments, and collaborative efforts such as a potential book on GPCR history.

Next steps

- Arthur will continue to collaborate with other researchers and drug companies to advance the understanding and application of allosteric modulation.

- Arthur will work on designing ligands for specific receptors, aiming to create biased agonists for therapeutic use.


Arthur's Career Journey and Allosteric Receptors

Yamina and Arthur discussed Arthur's career journey and his contributions to the field of pharmacology, with a focus on allosteric receptors and their modulation. Arthur highlighted his mentors' influence, such as Fred Mitchelson and Nigel Burch, and significant discoveries like the concept of synthetic allosteric modulators by Bruns and Fergus. He also discussed the evolution of the field, from biochemical radioligand binding assays to cell-based functional assays, and the influence of Terry Kenakin and chemical programs on his later work. The conversation ended with Arthur's ongoing research and his development of a new operational model. Yamina emphasized the importance of understanding the historical context of the field and the significance of Arthur's contributions.

Allosteric Modulation and Hybrid Molecules

Arthur and Yamina discussed the development of an operational model for allosteric modulation, emphasizing the balance between mechanism and empiricism. Arthur shared his career journey, including his collaboration with Patrick Sexton and Jim Burch, and the discovery of hybrid molecules with functional selectivity. They also discussed the re-emergence of interest in certain programs, the importance of connections across receptor families, and the potential of hybrid molecules. Arthur's strategy of consulting drug companies and targeting their posters at conferences was also shared with Yamina.

Pharmaceutical Industry Experiences and GPCR History

Arthur shared his experiences in the pharmaceutical industry, highlighting the differences between big pharma and biotech. They discussed strategies for analyzing large compound screening data, emphasizing robust assays and addressing issues like shifting curves. Arthur recounted a 2004 visit to a pharma company using replicates in assays. Yamina proposed compiling a book on GPCR history through collaborative interviews, considering a symposium to align terminology. For their upcoming project, Yamina favored a conversational approach, while Arthur suggested a kickoff meeting, with Yamina planning chapters and interviews.

Bias Mitigation in Symposium Ideas

Arthur and Yamina discussed the concept of bias in the context of the history of the Symposium idea. They reviewed significant early papers related to the topic, including work by Brian Roth, Terry Kenakin, Bill Clarke, and Kelly Burke. They also discussed their own research on chemokine receptors and the importance of understanding the natural environment in drug discovery. Lastly, they touched on a project with Nicola Smith that challenged their previous theories.

Allosteric Modulation and Drug Discovery

Yamina and Arthur delved into the complexities of protein-protein interactions, specifically allosteric modulation. They discussed various modulatory elements, such as RAMPs, G proteins, and GRKs, with Arthur recounting his initial collaboration with Patrick Sexton on RAMPs and amylin receptors. They also delved into the different signaling of Class B receptors and the potential for modulation at various levels. The discussion underscored the potential of allosteric modulators as drugs, despite challenges in the past due to a lack of understanding about the principles involved. They highlighted the importance of fine-tuning the approach to suit different diseases and interdisciplinary collaboration. The discussion also emphasized the need for a disease-specific approach, considering the clinical context and dialing in the desired effect, as well as the significance of rational drug design principles.

Allosteric Modulation and Autoantibodies Discussion

Arthur and Yamina discussed the potential of autoantibodies and allosteric modulation in the context of disease and therapeutic approaches. Arthur explained the concept of endogenous allosteric ligands and the possibility of using a neutral allosteric ligand as a preferred therapeutic approach, emphasizing the importance of looking for low level cooperativity factors. They also discussed the potential of certain drugs, like flumazenil, as 'nails' or compounds that could be developed into medicines. The conversation highlighted the importance of establishing the correct disease context, setting up appropriate assays, and understanding the models for their work. They both agreed on the necessity of understanding the target product for an allosteric modulator and working backwards from there.

TPP, Allosteric Modulators, and Reproducibility

Yamina and Arthur discussed the concept of a target product profile (TPP) in drug development, with Arthur explaining its application in other contexts as well. Yamina appreciated Arthur's expertise and indicated she would be creating an outline for an episode on allosteric modulators. They highlighted the importance of reproducibility in scientific experiments, sharing personal experiences and anecdotes. They also discussed their upcoming trips to the GPCR Colloquium in California and current research in their fields.

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