title: Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study.
abstract: N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases.
authors.affiliation: School of Biomedical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, UP, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: School of Biomedical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, UP, India. Electronic address: rpatnaik.bme@iitbhu.ac.in.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Patnaik
mesh_terms: D000495:Allosteric Site; D001812:Blood-Brain Barrier / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D000066829:Neuroprotection; D064209:Phytochemicals / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012855:Sitosterols / Q000737:chemistry; D032341:Withania / Q000737:chemistry*; D054358:Withanolides / Q000737:chemistry
chemical_list: C433551:3-rhamnopyranosyl(1-4)-glucopyranosyl-12-diacetoxy-20-hydroxywitha-5,24-dienolide; C485668:GRIN1 protein, human; D008024:Ligands; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D064209:Phytochemicals; D016194:Receptors, N-Methyl-D-Aspartate; D012855:Sitosterols; D054358:Withanolides; C010376:withanolide D; C025473:gamma-sitosterol; C009684:withaferin A
keywords: Allosteric inhibition; Excitotoxicity; N-methyl-d-aspartate receptors; Neurodegenerative diseases; Withania somnifera