title: Structural Characteristics of the Allosteric Binding Site Represent a Key to Subtype Selective Modulators of Muscarinic Acetylcholine Receptors.
abstract: The high conservation of the orthosteric acetylcholine binding site of muscarinic receptors (MAChR) represents a considerable challenge in terms of designing subtype selective drugs. A promising approach to gain subtype selectivity is to include allosteric or dualsteric targeting that aims to address more specific extracellular binding sites. Despite recent advances in crystallography of G protein coupled receptors (GPCRs), structural information for all 5 MAChR subtypes is not yet available. Here we report structural models of the active and the inactive receptor state of all subtypes derived by homology modelling in combination with MD simulations. The comparison of the allosteric binding site unveils the characteristics for each subtype on a structural level and indicates anchor points for rational design of selective drugs. Additionally, homology models offer the possibility for a rational explanation of dualsteric subtype selectivity, as we show for the M2 over M5 selectivity of the dualsteric ligands Atr-6-naph and Iper-6-phth.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany phone: +49 30 838 52686; fax: +49 30 838 452686.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bermudez
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany phone: +49 30 838 52686; fax: +49 30 838 452686.
authors.forename: Christin
authors.initials: C
authors.lastname: Rakers
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany phone: +49 30 838 52686; fax: +49 30 838 452686. gerhard.wolber@fu-berlin.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000235:genetics; D040681:Structural Homology, Protein
chemical_list: D011976:Receptors, Muscarinic
keywords: Drug design; Medicinal chemistry; Molecular dynamics; Protein models; Receptors