Nicotinic receptors: From protein allostery to computational neuropharmacology

Abstract

We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transitions of regulatory proteins to brain communications and specifically to neurotransmitters receptors, with the nicotinic acetylcholine receptor (nAChR) as a model of ligand-gated ion channels. The present development offers an expression of the change of the gating isomerization constant caused by pharmacological ligand binding in terms of its value in the absence of ligands and several "modulation factors", which vary with orthosteric ligand binding (agonists/antagonists), allosteric ligand binding (positive allosteric modulators/negative allosteric modulators) and receptor desensitization. The new - explicit - formulation of such "modulation factors", provides expressions for the pharmacological attributes of potency, efficacy, and selectivity for the modulatory ligands (including endogenous neurotransmitters) in terms of their binding affinity for the active, resting, and desensitized states of the receptor. The current formulation provides ways to design neuroactive compounds with a controlled pharmacological profile, opening the field of computational neuro-pharmacology.

Keywords: Allosteric regulation; Binding affinity calculations; Brain disease; Efficacy; MWC theory; Modeling; Molecular dynamics; Neuropharmacology; Nicotinic acetylcholine receptor; Potency; Selectivity; Synaptic receptors; Thermodynamic modeling.