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

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 in

SUBMITTER: Miao Y 

PROVIDER: S-EPMC4012891 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature