Albaret_1997_Proteins_28_543

Reference

Title : Molecular mechanic study of nerve agent O-ethyl S-[2- (diisopropylamino)ethyl]methylphosphonothioate (VX) bound to the active site of Torpedo californica acetylcholinesterase - Albaret_1997_Proteins_28_543
Author(s) : Albaret C , Lacoutiere S , Ashman WP , Froment D , Fortier PL
Ref : Proteins , 28 :543 , 1997
Abstract :

Herein a molecular mechanic study of the interaction of a lethal chemical warfare agent, O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (also called VX), with Torpedo californica acetylcholinesterase (TcAChE) is discussed. This compound inhibits the enzyme by phosphonylating the active site serine. The chirality of the phosphorus atom induces an enantiomeric inhibitory effect resulting in an enhanced anticholinesterasic activity of the SP isomer (VXS) versus its RP counterpart (VXR). As formation of the enzyme-inhibitor Michaelis complex is known to be a crucial step in the inhibitory pathway, this complex was addressed by stochastic boundary molecular dynamics and quantum mechanical calculations. For this purpose two models of interaction were analyzed: in the first, the leaving group of VX was oriented toward the anionic subsite of TcAChE, in a similar way as it has been suggested for the natural substrate acetylcholine; in the second, it was oriented toward the gorge entrance, placing the active site serine in a suitable position for a backside attack on the phosphorus atom. This last model was consistent with experimental data related to the high inhibitory effect of this compound and the difference in activity observed for the two enantiomers.

PubMedSearch : Albaret_1997_Proteins_28_543
PubMedID: 9261870

Related information

Inhibitor VX

Citations formats

Albaret C, Lacoutiere S, Ashman WP, Froment D, Fortier PL (1997)
Molecular mechanic study of nerve agent O-ethyl S-[2- (diisopropylamino)ethyl]methylphosphonothioate (VX) bound to the active site of Torpedo californica acetylcholinesterase
Proteins 28 :543

Albaret C, Lacoutiere S, Ashman WP, Froment D, Fortier PL (1997)
Proteins 28 :543