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 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.