title: In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile.
abstract: Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC(50) of NDGA on AChE was 46.2 μM. However, NDGA showed very poor central nervous system (CNS) activity and blood-brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD.
authors.affiliation: Department of Biotechnology and Microbiology and Inter University Centre for Biosciences, Kannur University, Thalassery Campus, Palayad P.O., Kerala 670661, India.
authors.forename: Chandran
authors.initials: C
authors.lastname: Remya
authors.forename: Kalarickal Vijayan
authors.initials: KV
authors.lastname: Dileep
authors.forename: Ignatius
authors.initials: I
authors.lastname: Tintu
authors.forename: Elessery Jayadevi
authors.initials: EJ
authors.lastname: Variyar
authors.forename: Chittalakkottu
authors.initials: C
authors.lastname: Sadasivan
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D032442:Larrea; D009637:Masoprocol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D028321:Plant Preparations / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D028321:Plant Preparations; D009637:Masoprocol; D000110:Acetylcholinesterase; D000109:Acetylcholine