Structure-based discovery of selective positive allosteric modulators of antagonists for the M₂ muscarinic acetylcholine receptor.

ABSTRACT: Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M₂ mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N-methyl scopolamine (NMS). Structure-based optimization led to compound '628, which enhanced binding of NMS, and the drug scopolamine itself, with a cooperativity factor (α) of

SUBMITTER: Korczynska M 

PROVIDER: S-EPMC5877965 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature