US EPA

7422231 

Journal Article 

A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs 

Lee, S; Barron, MG; , 

2016 

Yes 

Journal of Computer-Aided Molecular Design
ISSN: 0920-654X
EISSN: 1573-4951 

SPRINGER 

DORDRECHT 

30 

4 

347-363 

English 

27055524 

10.1007/s10822-016-9910-7 

WOS:000374413900007 

http://link.springer.com/10.1007/s10822-016-9910-7
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Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π-π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency. 

3D-fingerprint; 3D-QSAR; Acetylcholinesterase inhibitor; Mechanism-based; Molecular docking; Pharmacophore; acetylcholinesterase; carbamic acid derivative; organophosphate; acetylcholinesterase; carbamic acid derivative; cholinesterase inhibitor; insecticide; organophosphate; pesticide; serine; Article; conformational transition; covalent bond; enzyme inhibition; hydrogen bond; metabolic activation; molecular docking; priority journal; quantitative structure activity relation; chemistry; computer simulation; drug effects; enzyme active site; molecular model; quantitative structure activity relation; Acetylcholinesterase; Carbamates; Catalytic Domain; Cholinesterase Inhibitors; Computer Simulation; Hydrogen Bonding; Insecticides; Models, Molecular; Organophosphates; Pesticides; Quantitative Structure-Activity Relationship; Serine