Rational design of dualsteric GPCR ligands: quests and promise

British Journal of Pharmacology
Klaus MohrUlrike Holzgrabe

Abstract

Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dua...Continue Reading

References

Nov 1, 1976·British Journal of Pharmacology·A L Clark, F Mitchelson
Oct 24, 1991·Biochemical Pharmacology·J EllisM R Brann
Feb 1, 1983·British Journal of Pharmacology·N J M BirdsallM J Zigmond
Jan 1, 1993·Life Sciences·G LambrechtE Mutschler
Aug 1, 1996·Trends in Pharmacological Sciences·Evi Kostenis, Klaus Mohr
Dec 13, 1996·Biochemical Pharmacology·A L Gnagey, J Ellis
Jan 1, 1997·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·J C GoinL Sterin-Borda
Sep 11, 1999·Bioorganic & Medicinal Chemistry·Clelia DallanoceM Impicciatore
Apr 6, 2001·European Journal of Pharmacology·A LanzafameF Mitchelson
Apr 19, 2002·The Journal of Pharmacology and Experimental Therapeutics·Katrin ZahnKlaus Mohr
Jun 27, 2003·Journal of Computer-aided Molecular Design·Kirstin Jöhren, Hans-Dieter Höltje
Aug 2, 2003·Receptors & Channels·Klaus MohrUlrike Holzgrabe
Aug 6, 2004·Journal of Medicinal Chemistry·Chouaib TahtaouiBrigitte Ilien
Jun 25, 2005·Mini Reviews in Medicinal Chemistry·N J M Birdsall, S Lazareno
Jan 13, 2006·Annual Review of Pharmacology and Toxicology·Thue W SchwartzChristian E Elling
Apr 4, 2006·Drug Discovery Today·Zhan-Guo Gao, Kenneth A Jacobson
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
May 26, 2007·Molecular Pharmacology·Lauren T MayArthur Christopoulos
Jul 17, 2007·Trends in Pharmacological Sciences·Brian K Kobilka, Xavier Deupi
Sep 1, 2007·Nature Reviews. Drug Discovery·Jürgen WessDinesh Gautam
May 2, 2008·British Journal of Pharmacology·S P H AlexanderJ A Peters
Nov 1, 1989·Trends in Endocrinology and Metabolism : TEM·E M Dax
Aug 15, 2008·Journal of Receptor and Signal Transduction Research·Ciria C HernandezLuis E Gimenez
Oct 8, 2008·Trends in Pharmacological Sciences·Jürgen WessJian Hua Li
Oct 10, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Johannes AntonyKlaus Mohr
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Jan 6, 2009·Drug Discovery Today·Ralf HeilkerMichael Bieler
May 22, 2009·Nature·Daniel M RosenbaumBrian K Kobilka
Jul 10, 2009·Journal of Receptor and Signal Transduction Research·Anna KebigMarion Mohr-Andrä
Dec 24, 2009·Current Pharmaceutical Design·Irina G Tikhonova, Stefano Costanzi

Citations

May 29, 2012·Journal of Medicinal Chemistry·Amy Hauck NewmanLei Shi
May 18, 2013·Journal of Medicinal Chemistry·Christine HillerPeter Gmeiner
Jul 28, 2013·Molecular Pharmacology·Andrew C KruseBrian K Shoichet
Oct 12, 2013·Annual Review of Pharmacology and Toxicology·Cody J WenthurCraig W Lindsley
Mar 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Celine ValantArthur Christopoulos
Aug 12, 2014·Nature Chemical Biology·J Robert LaneArthur Christopoulos
Sep 14, 2011·Annual Review of Pharmacology and Toxicology·Celine ValantArthur Christopoulos
Jun 7, 2014·Nature Reviews. Drug Discovery·Andrew C KruseJürgen Wess
Feb 3, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·André S PupoClaudio M Costa-Neto
Sep 21, 2013·Drug Discovery Today. Technologies·Andreas Bock, Klaus Mohr
Nov 28, 2012·Trends in Pharmacological Sciences·J Robert LaneArthur Christopoulos
Jun 26, 2012·Pharmacology & Therapeutics·Christa E MüllerYounis Baqi
Jan 13, 2011·Progress in Biophysics and Molecular Biology·Gábor Maksay
Jul 20, 2010·Neuropharmacology·Peter KeovArthur Christopoulos
Jul 16, 2010·Chemical Biology & Drug Design·Anthony Ivetac, J Andrew McCammon
Oct 16, 2012·British Journal of Pharmacology·R SchrageKlaus Mohr
Mar 22, 2016·Biochemical Pharmacology·Rosanna MatucciMaria Novella Romanelli
May 30, 2013·British Journal of Pharmacology·A J KooistraC de Graaf
Apr 15, 2010·British Journal of Pharmacology·R J Summers
Jan 26, 2016·British Journal of Pharmacology·Georges VauquelinDavid C Swinney
Dec 28, 2010·Biochemical Pharmacology·Neil T BurfordAndrew Alt
Jan 24, 2016·Chemical Biology & Drug Design·Annu MudgalSantosh Pasha
Jun 15, 2016·Chemical Reviews·Graeme MilliganBrian D Hudson
May 3, 2016·British Journal of Clinical Pharmacology·Georges Vauquelin
Nov 24, 2016·Medicinal Research Reviews·Thuy NguyenYanan Zhang
Mar 5, 2014·Chemistry & Biodiversity·Thomas TrögerChristoph Enzensperger
Oct 17, 2012·Médecine sciences : M/S·Jean-Luc Galzi, Brigitte Ilien
Aug 1, 2013·Molecular Informatics·Agnieszka A KaczorManuel Pastor
Jul 26, 2014·Molecular Pharmacology·Arthur Christopoulos
Jun 24, 2015·The Journal of Biological Chemistry·Patrick R GentryArthur Christopoulos
Apr 20, 2018·Molecular Informatics·Giuseppe DeganuttiStefano Moro
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Daniela Volpato, Ulrike Holzgrabe
Apr 27, 2011·ChemMedChem·Jeremy ShonbergBen Capuano
Oct 29, 2020·Nature Communications·Qingpin XiaoCheng Zhang
Feb 18, 2021·Journal of Natural Products·Darius Paul ZlotosUlrike Holzgrabe
Mar 18, 2020·European Journal of Pharmacology·Carlo MateraSimona Bertoni
Feb 24, 2021·The FEBS Journal·Andreas Bock, Marcel Bermudez

Related Concepts

Allosteric Site
Ligands
Plasma Protein Binding Capacity
Drug Modeling
Drug Delivery Systems
G-Protein-Coupled Receptors
Allosteric Regulation
Muscarinic Acetylcholine Receptor
Signal Pathways
Spatial Distribution

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