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

Neurotoxic organophosphorous compounds are known to modulate their biologic al effects through the inhibition of a number of esterases including acetyl cholinesterase (AChE), the enzyme responsible for the degradation of the ne urotransmitter acetylcholine. In this light, molecular modeling studies wer e performed on a collection of organophosphorous acetylcholinesterase inhib itors by the combined use of conformational analysis and 3D-QSAR methods to rationalize their inhibitory potencies against the enzyme. The Catalyst pr ogram was used to identify the structural features in the group of 8 inhibi tors whose IC50 values ranged from 0.34 nM to 1.2 muM. The 3-D pharmacophor e models are characterized by at least one hydrogen bond acceptor site and 2-3 hydrophobic sites and demonstrate very good correlation between the pre dicted and experimental IC50 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 a gents for central nervous system diseases.