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.

Keywords: Chiral organophosphates; Enantioselectivity; In vitro testing; Molecular docking; Virtual screening.