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Bridging the gap: bitopic ligands of G-protein-coupled receptors

Lane, J Robert; Sexton, Patrick M; Christopoulos, Arthur


Associate Professor

Patrick M Sexton

Arthur Christopoulos


Although classical approaches to G-protein-coupled receptor (GPCR) drug design have targeted the orthosteric binding site, potentially all GPCRs possess druggable allosteric sites. In addition, it is clear that GPCRs can adopt multiple active states linked to distinct functional outcomes that can be stabilized by both allosteric and orthosteric ligands. Recent studies have begun to explore the possibilities of linking orthosteric and allosteric pharmacophores to yield 'bitopic' ligands as an approach to achieve improved receptor affinity or selectivity. Furthermore, it is possible that previously identified functionally selective drugs may represent unappreciated bitopic ligands at this important class of drug targets. Here we discuss both the potential of bitopic ligands in GPCR drug discovery and the challenges associated with the design of such ligands.


Lane, J. R., Sexton, P. M., & Christopoulos, A. (2013). Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends in Pharmacological Sciences, 34(1), 59-66.

Journal Article Type Review
Online Publication Date Nov 21, 2012
Publication Date Jan 1, 2013
Deposit Date Apr 22, 2020
Print ISSN 0165-6147
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 34
Issue 1
Pages 59-66
Public URL
Publisher URL