Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor.

ABSTRACT: Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Institute (NCI) were docked to the receptor ensembles. Retrospective docking of known ligands showed that combining aMD simulations with Glide induced fit docking (IFD) provided much-improved enrichment fac

SUBMITTER: Miao Y 

PROVIDER: S-EPMC5035859 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature