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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.

The number of applications of computational techniques to medicinal chemistry is growing rapidly. Quantitative Structure‐Activity Relationships (QSAR) have been used very successfully to correlate structural features to biological activities. A type of QSAR, Linear Solvation Energy Relationships (LSER) has been used to correlate a large number and wide variety of biological properties. Famini and Wilson have developed a theoretical extension of the LSER, called the TLSER, that incorporates only computationally derived descriptors. We have applied the TLSER methodology to a series of fentanyl‐like compounds that exhibit activity at the opiate receptor. TLSER correlations of the entire data set, as well as specific subsets are considered.

Molecular mechanics provides an excellent means of generating reasonable chemical structures in a short amount of time. Using a classical representation, a molecule can be partitioned into a collection of n-fold atomic interactions, each with an associated force constant. In order for a calculation to proceed, all of the required force constants must be known. This article presents a method of rapidly determining the values for missing parameters using appropriately scaled quantum chemical techniques.

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