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Drug‐like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase
Author(s) -
Wildman Scott A.,
Zheng Xiange,
Sept David,
Auletta Jeffrey T.,
Rosenberry Terrone L.,
Marshall Garland R.
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01157.x
Subject(s) - active site , binding site , serine hydrolase , acetylcholinesterase , virtual screening , chemistry , docking (animal) , serine , organophosphate , steric effects , stereochemistry , biochemistry , enzyme , drug discovery , biology , medicine , nursing , pesticide , agronomy
Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P‐site) near the mouth of the active‐site gorge. Compounds that bind to this site may selectively block access to the acylation site (A‐site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using A uto D ock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A‐site or P‐site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A‐site only and in both and A‐ and P‐sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P‐site in an inhibitor competition assay.