Computational binding study with α7 nicotinic acetylcholine receptor of Anvylic-3288: an allosteric modulator

Nicotinic receptors are ligand-gated ion channels, involved in the generation of action potential in post synaptic membrane and motor endplate. The alpha 7 Nicotinic Acetylcholine Receptor (nAChR) is a class of nicotinic receptor involved in cognition. It is distributed in hippocampus, thalamus, sensory and information processing regions of the brain. The receptor is implicated in various diseases, including Alzheimer's disease, Parkinsonism, Schizophrenia, Autism, Rett syndrome etc. Therefore, targeting the modulation of the receptor would be advantageous. Positive allosteric modulators (PAMs) potentiate the response i.e. peak current of the receptor. Type I allosteric modulator, Anvylic-3288 (AVL-3288), increases peak current without altering the response of alpha 7-nAChR upon acetylcholine binding. In present study,in silicoapproach was used to identify the plausible binding model of AVL-3288 involved in modulation. Docking study displayed that a1 binding modes had better binding energies than the t1 and v1 modes. The MD (Molecular Dynamics) simulation produced stable complex for a1 pose, binding to agonist subpocket, with alpha 7-nAChR having protein and ligand RMSD (Root Mean Square Deviation) in the acceptable limits, and comparable to MM/PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) results.