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Abstract

The M2 muscarinic acetylcholine receptor belongs to the family of rhodopsin like G-Protein Coupled Receptors. This subtype of muscarinic receptors is of special interest because it bears, aside from an orthosteric binding site, also an allosteric binding site. Based on the X-ray structure of bovine rhodopsin a complete homology model of the human M2 receptor was developed. For the orthosteric binding site point mutations and binding studies with different agonists and antagonists are available. This knowledge was utilized for an initial verification of the M2 model. Allosteric modulation of activity is mediated by structurally different ligands such as gallamine, caracurine V salts or W84 (a hexamethonium-derivative). Caracurine V derivatives with different affinities to M2 were docked using GRID-fields. Subsequent molecular dynamics simulations yielded different binding energies based on diverse electrostatic and lipophilic interactions. The calculated affinities are in good agreement to experimentally determined affinities.

Muscarinic Receptors: A Comparative Analysis of Structural Features and Binding Modes through Homology Modelling and Molecular Docking

“…The ester function forms H-bonds with Tyr104 and Ser107 of TM3, while the role of threonine residues in TM5 (i.e., Thr187 and Thr190) is doubtful both in our model and from experimental data [22]. The model proposed by Johren and Hçltje suggested that the threonine residues in TM5 may be involved in interaction with antagonist (S)-scopolamine [18].…”

“…In recent years, several reliable GPCR homology models appeared in literature, showing that they can be successfully used for virtual screening and ligand optimization [15] [16]. In particular, a homology model of the M 1 subtype was reported by Hulme et al [17], and a M 2 receptor model was proposed by Johren and Hçltje [18]. Several models of the sole transmembrane bundle of muscarinic receptors were published [15], but they seem somewhat outdated due to the current opportunity to build complete models.…”

Molecular Modeling of the M3 Acetylcholine Muscarinic Receptor and Its Binding Site

“…NMS was docked onto the binding pocket of M3R taking into account the residues known to affect its binding from site-directed mutagenesis studies, specifically D 3.32 known to interact with the ligand quaternary nitrogen [52], N 6.52 putatively involved in a polar interaction with the ligand [53–55], and the homologous hydrophobic residues implicated in the binding of NMS at the M1 muscarinic receptor [56]. Once docked, the complex was energy minimized and the MD simulation started.…”

Allosteric Modulation of Muscarinic Acetylcholine Receptors

“…Othosteric antagonists with N to carboxyl C distances over 500 pm (NMS, 4-diphenylacetoxy- N -dimethylpiperidium, and N -methylpiperidyl benzylate) displayed positive, while orthosteric ligands with N to carboxyl C distances less than 500 pm ( N -methylquinuclidinyl benzilate, quinuclidinyl benzylate, and acetylcholine) displayed negative binding cooperativity with alcuronium ( 3 ; Figure 1) [61]. According to docking of orthosteric ligands to homology models of the M 2 receptor and knowledge from mutagenesis studies, the nitrogen group of orthosteric ligands interacts with aspartic acid in the TM3 domain and the carboxyl group of orthosteric ligands interacts with residues in the TM6 domain [62]. Thus data suggest that allosteric modulators change orientation of the TM3 and TM6 domains.…”