Nicotinic acetylcholine receptor (nAChR) agonists act at an “orthosteric” binding site located in the extracellular vestibule in the cleft between two adjacent subunits. Especially for the homomeric a7 nAChR channel, several ligands have been also identified which affect the functional receptor response by interacting with a transmembrane “allosteric” recognition site. These ligands, known as positive allosteric modulators (PAMs), increase both sensitivity to receptor agonists and current amplitude. Type I PAMs exert their action increasing the current intensity evoked by ACh without altering the kinetics of desensitization. On the other hand, type II PAMs, in addition to increasing several times the maximum amplitude and power of the induced current, almost completely suppress desensitization. Moreover, since a prolonged contact with an agonist (i.e., nicotine or ACh) desensitizes the a7-‐nAChR and reduces the response to an undetectable level, the application of a type II PAM during a continuous exposure to an agonist may restore a peak of power even greater than that induced by the agonist alone. Quite recently, some analogues of the type II PAM TQS were reported, which are able to activate the a7 channel even in the absence of orthosteric ligands, at variance with the classical allosteric activators. They are called “ago-‐PAM” and GAT107, the active (+) enantiomer of 4BP-‐TQS, seems to be most interesting term of these derivatives.1 In this study, the application of various computational approaches allowed to investigating the binding modes of the classical type-‐II PAM (PNU-‐120596), GAT107 and its inactive enantiomer (Figure 1). By means of metadynamic simulations we analyzed: 1) the conformational free energy landscape of a loop sizing the orthosteric site (loop C), and 2) if this is influenced by the presence of ligands bound to the allosteric site. Finally, we applied essential dynamics and Principal Component Analysis to uncover some aspects of the α7-‐nAChR functional mechanism. The results of this investigation may contribute to clarify the reciprocal communications between the orthosteric and allosteric recognition sites of homomeric nicotinic channels, and will be exploited to rationally design novel PAMs targeting the a7 receptor subtype.
Ago-allosteric modulation of nicotinic alpha7 receptors : a mechanistic insight by metadynamics and essential dynamics / G. Grazioso. ((Intervento presentato al 8. convegno Meeting nuove prospettive in chimica farmaceutica tenutosi a Parma nel 2014.
Ago-allosteric modulation of nicotinic alpha7 receptors : a mechanistic insight by metadynamics and essential dynamics
G. Grazioso
2014
Abstract
Nicotinic acetylcholine receptor (nAChR) agonists act at an “orthosteric” binding site located in the extracellular vestibule in the cleft between two adjacent subunits. Especially for the homomeric a7 nAChR channel, several ligands have been also identified which affect the functional receptor response by interacting with a transmembrane “allosteric” recognition site. These ligands, known as positive allosteric modulators (PAMs), increase both sensitivity to receptor agonists and current amplitude. Type I PAMs exert their action increasing the current intensity evoked by ACh without altering the kinetics of desensitization. On the other hand, type II PAMs, in addition to increasing several times the maximum amplitude and power of the induced current, almost completely suppress desensitization. Moreover, since a prolonged contact with an agonist (i.e., nicotine or ACh) desensitizes the a7-‐nAChR and reduces the response to an undetectable level, the application of a type II PAM during a continuous exposure to an agonist may restore a peak of power even greater than that induced by the agonist alone. Quite recently, some analogues of the type II PAM TQS were reported, which are able to activate the a7 channel even in the absence of orthosteric ligands, at variance with the classical allosteric activators. They are called “ago-‐PAM” and GAT107, the active (+) enantiomer of 4BP-‐TQS, seems to be most interesting term of these derivatives.1 In this study, the application of various computational approaches allowed to investigating the binding modes of the classical type-‐II PAM (PNU-‐120596), GAT107 and its inactive enantiomer (Figure 1). By means of metadynamic simulations we analyzed: 1) the conformational free energy landscape of a loop sizing the orthosteric site (loop C), and 2) if this is influenced by the presence of ligands bound to the allosteric site. Finally, we applied essential dynamics and Principal Component Analysis to uncover some aspects of the α7-‐nAChR functional mechanism. The results of this investigation may contribute to clarify the reciprocal communications between the orthosteric and allosteric recognition sites of homomeric nicotinic channels, and will be exploited to rationally design novel PAMs targeting the a7 receptor subtype.
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
