Investigation of Muscarinic Acetylcholine Receptor M₃ Activation in Atomistic Detail: A Chemist's Viewpoint.

ABSTRACT: We analyzed the precise ligand:receptor interactions required for activation of the muscarinic acetylcholine receptor M₃, a prototypical G protein-coupled receptor and potential diabetes target. Starting from literature-known compounds and docking solutions, ligands were tailored for the modulation of this receptor's activation. Several aspects of the structure-activity relationship of agonists were investigated in atomistic detail, in order to delineate how the receptor can be activated via the orthosteric site. Such exquisitely precise knowledge is instrumental for designing potent and effiacious ligands. We put this strategy into practice and acquired or synthesized and measured a diverse set of 55 ligands ranging from small fragment-like amines coordinating D^3.32

SUBMITTER: Drabek M 

PROVIDER: S-EPMC11793849 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature