Drug-like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase

Scott A. Wildman, Xiange Zheng, David Sept, Jeffrey T. Auletta, Terrone L. Rosenberry, Garland R. Marshall

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)495-504
Number of pages10
JournalChemical Biology and Drug Design
Volume78
Issue number4
DOIs
StatePublished - Oct 2011

Fingerprint

Cholinesterase Inhibitors
Acetylcholinesterase
Acylation
Acetylcholine
Binding Sites
Screening
Substrates
Pharmaceutical Preparations
Catalytic Domain
Chemical Warfare Agents
Organophosphates
Poisons
Enzymes
Insecticides
Serine
Mouth
Assays
Testing

Keywords

  • Acetylcholine
  • Acetylcholinesterase
  • AChE
  • Docking
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Drug-like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase. / Wildman, Scott A.; Zheng, Xiange; Sept, David; Auletta, Jeffrey T.; Rosenberry, Terrone L.; Marshall, Garland R.

In: Chemical Biology and Drug Design, Vol. 78, No. 4, 10.2011, p. 495-504.

Research output: Contribution to journalArticle

Wildman, Scott A. ; Zheng, Xiange ; Sept, David ; Auletta, Jeffrey T. ; Rosenberry, Terrone L. ; Marshall, Garland R. / Drug-like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase. In: Chemical Biology and Drug Design. 2011 ; Vol. 78, No. 4. pp. 495-504.
@article{efc4b608c51a47bfbbc2c601455e4cc0,
title = "Drug-like Leads for Steric Discrimination between Substrate and Inhibitors of Human Acetylcholinesterase",
abstract = "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.",
keywords = "Acetylcholine, Acetylcholinesterase, AChE, Docking, Virtual screening",
author = "Wildman, {Scott A.} and Xiange Zheng and David Sept and Auletta, {Jeffrey T.} and Rosenberry, {Terrone L.} and Marshall, {Garland R.}",
year = "2011",
month = "10",
doi = "10.1111/j.1747-0285.2011.01157.x",
language = "English (US)",
volume = "78",
pages = "495--504",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "4",

}

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 - Acetylcholine

KW - Acetylcholinesterase

KW - AChE

KW - Docking

KW - Virtual screening

UR - http://www.scopus.com/inward/record.url?scp=84860416346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.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

VL - 78

SP - 495

EP - 504

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 4

ER -