Computational binding study with α7 nicotinic acetylcholine receptor of Anvylic-3288: an allosteric modulator. Issue 13 (1st September 2020)

• Record Type: Journal Article
• Authors: Ganeshpurkar, Ankit; Singh, Ravi; Kumar, Devendra; Divya, ; Shivhare, Shalini; Kumar, Ashok; Singh, Sushil Kumar
• Is Part Of: Molecular simulation. Volume 46:Issue 13(2020)
• Page Start: 975
• Page End: 986
• Publication Date: 2020-09-01
• Subjects: AVL-3288 -- positive allosteric modulators -- α7-nAChR -- Amber -- docking; Molecular dynamics -- Computer simulation -- Periodicals; Statistical mechanics -- Computer simulation -- Periodicals; 539.6
• DOI: 10.1080/08927022.2020.1795166
• Languages: English
• ISSNs: 0892-7022

Abstract

ABSTRACT: Nicotinic receptors are ligand-gated ion channels, involved in the generation of action potential in post synaptic membrane and motor endplate. The α7 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 α7-nAChR upon acetylcholine binding. In present study, in silico approach 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 α7-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.