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Dynamic bias and its implications for GPCR drug discovery

Nature Reviews Drug Discovery volume 13, page 869 (2014)Cite this article

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In their Opinion article (Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nature Rev. Drug Discov. 12, 205–216 (2013)) 1, Kenakin and Christopoulos provide a detailed explanation of ligand bias, where a ligand preferentially stimulates certain G protein-coupled receptor (GPCR)-activated signalling pathways over others. Although the Review acknowledges system bias and observational bias as aspects that may prevent the accurate definition of ligand bias, one aspect that was not discussed was that produced by the dynamic nature of in vivo systems.

GPCR expression, compartmentalization and function are dynamically regulated by physiological and pathophysiological factors, as well as by treatments, and this regulation also applies to the expression of specific G proteins and arrestins. Changes in such regulation will affect the stoichiometry of GPCRs with downstream signalling pathways, as well as the spontaneous level of receptor activity; together, these effects represent something we propose calling 'dynamic bias'.

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Authors and Affiliations

  1. Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, Mainz, 51101, Germany

    Martin C. Michel

  2. Department of Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, D-30625, Germany

    Roland Seifert

  3. Department of Pharmacology and Pharmaceutical Sciences, Science and Research Building 2, Room 521, University of Houston, Houston, 77204–5037, Texas, USA

    Richard A. Bond

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  1. Martin C. Michel
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  2. Roland Seifert
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Correspondence to Richard A. Bond.

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Competing interests

M.C.M. is an employee of Boehringer Ingelheim. R.A.B. is a shareholder of Invion. R.S. declares no competing interests.

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Michel, M., Seifert, R. & Bond, R. Dynamic bias and its implications for GPCR drug discovery. Nat Rev Drug Discov 13, 869 (2014). https://doi.org/10.1038/nrd3954-c3

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