title: An enantiomer-based virtual screening approach: Discovery of chiral organophosphates as acetyl cholinesterase inhibitors.
abstract: Chiral organophosphates (OPs) have been used widely around the world, very little is known about binding mechanisms with biological macromolecules. An in-depth understanding of the stereo selectivity of human AChE and discovering bioactive enantiomers of OPs can decrease health risks of these chiral chemicals. In the present study, a flexible molecular docking approach was conducted to investigate different binding modes of twelve phosphorus enantiomers. A pharmacophore model was then developed on basis of the bioactive conformations of these compounds. After virtual screening, twenty-four potential bioactive compounds were found, of which three compounds (Ethyl p-nitrophenyl phenylphosphonate (EPN), 1-naphthaleneacetic anhydride and N,4-dimethyl-N-phenyl-benzenesulfonamide) were tested by use of different in vitro assays. S-isomer of EPN was also found to exhibit greater inhibitory activity towards human AChE than the corresponding R-isomer. These findings affirm that stereochemistry plays a crucial role in virtual screening, and provide a new insight into designing safer organ phosphorus pesticides on human health.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Aiqian
authors.initials: A
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China. Electronic address: muyunsong323@163.com.
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
authors.forename: Fengchang
authors.initials: F
authors.lastname: Wu
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009280:Naphthaleneacetic Acids / Q000737:chemistry / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry* / Q000494:pharmacology; D009943:Organophosphorus Compounds; D010575:Pesticides / Q000737:chemistry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D009280:Naphthaleneacetic Acids; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010575:Pesticides; D013449:Sulfonamides; C023604:phenylphosphonic acid; D000110:Acetylcholinesterase
keywords: Chiral organophosphates; Enantioselectivity; In vitro testing; Molecular docking; Virtual screening