Prediction of organophosphorus acetylcholinesterase inhibition using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods

Neurotoxic organophosphorous compounds are known to modulate their biological effects through the inhibition of a number of esterases including acetylcholinesterase (AChE), the enzyme responsible for the degradation of the neurotransmitter acetylcholine. In this light, molecular modeling studies wer...

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Bibliographic Details
Published in:Toxicological sciences 2001-10, Vol.63 (2), p.223-232
Main Authors: EL YAZAL, Jamal, RAO, Shashidhar N, MEHL, Adrea, SLIKKER, William JR
Format: Article
Language:English
Subjects:
Algorithms
Binding Sites
Biological and medical sciences
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - metabolism
Computer Simulation
Crystallography, X-Ray
Databases, Factual
Drug Design
Humans
Hydrogen Bonding
Medical sciences
Models, Molecular
Models, Structural
Molecular Conformation
Molecular Weight
Neuroblastoma
Organophosphorus Compounds - pharmacology
Pesticides, fertilizers and other agrochemicals toxicology
Predictive Value of Tests
Quantitative Structure-Activity Relationship
Reproducibility of Results
Statistics as Topic
Thermodynamics
Toxicology
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Summary:Neurotoxic organophosphorous compounds are known to modulate their biological effects through the inhibition of a number of esterases including acetylcholinesterase (AChE), the enzyme responsible for the degradation of the neurotransmitter acetylcholine. In this light, molecular modeling studies were performed on a collection of organophosphorous acetylcholinesterase inhibitors by the combined use of conformational analysis and 3D-QSAR methods to rationalize their inhibitory potencies against the enzyme. The Catalyst program was used to identify the structural features in the group of 8 inhibitors whose IC(50) values ranged from 0.34 nM to 1.2 microM. The 3-D pharmacophore models are characterized by at least one hydrogen bond acceptor site and 2-3 hydrophobic sites and demonstrate very good correlation between the predicted and experimental IC(50) values. Our models can be useful in screening databases of organophosphorous compounds for their neurotoxicity potential via the inhibition of acetylcholinesterase. Also, the pharmacophores offer an additional means of designing AChE inhibitors as potential therapeutic agents for central nervous system diseases.
ISSN:1096-6080
1096-0929
1096-0929
DOI:10.1093/toxsci/63.2.223