G-protein coupled receptors (GPCRs) represent on of the most successful therapeutic target families, including approximately 30 % of all known drug targets covering a wide range of therapeutic fields [1]. GPCRs trigger multiple signal-switching mechanisms, not only G-protein activation but also binding of �-arrestin proteins and activation of kinases. Surprisingly the understanding of the conformational changes resulting in these activations is very poor and remains a major challenge for the design of specific GPCR modulating drugs. The recently published crystal structure of the M2 muscarinic acetylcholine receptor (PDB: 3UON [2]) and mutational studies provides the possibility to rationalize and understand the binding of ligands to muscarinic acetylcholine receptors, explain their subtype preference and give insights into the flexibility of their binding pockets.We present the results of extensive molecular dynamics (MD) simulations in combination with molecular docking and 3D-pharmacophore analysis of known ligands and related structures. The orientation of the tropane ring system plays an essential role for the arrangement of the whole ligand, resulting in subtype specific binding modes. These findings were in accordance with binding experiments and mutational data. [1] Jacoby, E., et al.: The 7TM G-protein-coupled receptor target family. Chemmedchem, 2006, 1(8):760-782.[2] Haga, K., et al.: Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature, 2012, 482(7386).

Molecular modeling of subtype selective muscarinic antagonists

248th National Meeting (2014)

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