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Chem Biol Drug Des. 2014 Feb;83(2):237-46. doi: 10.1111/cbdd.12233. Epub 2013 Oct 30.

Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor.

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  • 1Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, 92093, USA.

Abstract

G-protein-coupled receptors (GPCRs) are key cellular signaling proteins and have been targeted by approximately 30-40% of marketed drugs for treating many human diseases including cancer and heart failure. Recently, we directly observed activation of the M2 muscarinic receptor through long-timescale accelerated molecular dynamics (aMD) simulation, which revealed distinct inactive, intermediate and active conformers of the receptor. Here, FTMAP is applied to search for 'hot spots' in these activation-associated conformers using a library of 16 organic probe molecules that represent fragments of potential drugs. Seven allosteric (non-orthosteric) binding sites are identified in the M2 receptor through the FTMAP analysis. These sites are distributed in the solvent-exposed extracellular and intracellular mouth regions, as well as the lipid-exposed pockets formed by the transmembrane α helices TM3-TM4, TM5-TM6 and TM7-TM1/TM2. They serve as promising target sites for designing novel allosteric modulators as receptor-selective drugs.

© 2013 John Wiley & Sons A/S.

KEYWORDS:

FTMAP; GPCR; M2 muscarinic receptor; accelerated molecular dynamics; allosteric sites; receptor-selective drugs

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