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Structural Characteristics of the Allosteric Binding Site Represent a Key to Subtype Selective Modulators of Muscarinic Acetylcholine Receptors
Author(s) -
Bermudez Marcel,
Rakers Christin,
Wolber Gerhard
Publication year - 2015
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201500025
Subject(s) - allosteric regulation , homology modeling , muscarinic acetylcholine receptor , binding site , chemistry , g protein coupled receptor , rational design , receptor , binding pocket , drug discovery , acetylcholine receptor , computational biology , biophysics , biochemistry , biology , genetics , enzyme
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 M 2 over M 5 selectivity of the dualsteric ligands Atr‐6‐naph and Iper‐6‐phth.