TY - JOUR
T1 - Drug-like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase
AU - Wildman, Scott A.
AU - Zheng, Xiange
AU - Sept, David
AU - Auletta, Jeffrey T.
AU - Rosenberry, Terrone L.
AU - Marshall, Garland R.
PY - 2011/10
Y1 - 2011/10
N2 - 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 AutoDock 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. Virtual screening was used to identify selective peripheral-site inhibitors of acetylcholinesterase. The best hit compound was demonstrated to bind in the presence of acetylcholine by the creation of the tripartite AChE-inhibitor-acetylcholine complex.
AB - 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 AutoDock 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. Virtual screening was used to identify selective peripheral-site inhibitors of acetylcholinesterase. The best hit compound was demonstrated to bind in the presence of acetylcholine by the creation of the tripartite AChE-inhibitor-acetylcholine complex.
KW - AChE
KW - Acetylcholine
KW - Acetylcholinesterase
KW - Docking
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=84860416346&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2011.01157.x
DO - 10.1111/j.1747-0285.2011.01157.x
M3 - Article
C2 - 21668653
AN - SCOPUS:84860416346
SN - 1747-0277
VL - 78
SP - 495
EP - 504
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 4
ER -