Journal:CHEMBIOINT:2

Molecular Dynamics Simulations of the Interaction of Mouse and Torpedo Acetylcholinesterase with Covalent Inhibitors Explain Their Differential Reactivity: Implications for Drug Design

Nellore Bhanu Chandar, Irena Efremenko, Israel Silman, Jan M. L. Martin, and Joel L. Sussman ^[1]

Molecular Tour
Although the (TcAChE (1ea5) in blue, and mAChE (5dti) in orange), their responses to the covalent sulfonylating agents benzenesulfonyl fluoride and phenylmethylsulfonyl fluoride are qualitatively different. Both agents inhibit the mouse enzyme effectively by covalent modification of its active site serine. In contrast, whereas the Torpedo enzyme is effectively inhibited by benzenesulfonyl fluoride, it is almost completely resistant to phenylmethylsulfonyl fluoride. A bottleneck midway down the active-site gorge in both enzymes restricts access of ligands to the active site at the bottom of the gorge. Molecular dynamics simulations revealed that the mouse enzyme is substantially more flexible than the Torpedo enzyme, suggesting that enhanced ‘breathing motions’ of the mouse enzyme relative to the Torpedo enzyme may explain why phenylmethylsulfonyl fluoride can reach the active site in mouse acetylcholinesterase, but not in the Torpedo enzyme. Accordingly, we performed docking of the two sulfonylating agents to the two enzymes, followed by molecular dynamics simulations. Whereas benzenesulfonyl fluoride closely approaches the active-site serine in both mouse and Torpedo acetylcholinesterase in such simulations, phenylmethylsulfonyl fluoride is able to approach the active-site serine of mouse acetylcholinesterase, but remains trapped above the bottleneck in the Torpedo enzyme. Our studies demonstrate that reliance on docking tools in drug design can produce misleading information. Docking studies should, therefore, also be complemented by molecular dynamics simulations in selection of lead compounds.

GlideXP docking and MD simulation for interaction of BSF and PMSF with TcAChE and mAChE. In all four scenes two copies of the ligand are displayed. One shows the position of the ligand after docking alone (blue), and the other shows the position after docking followed by MD simulation (orange). It should be noted that the orientations of the amino-acid side-chains displayed are those seen prior to the MD simulations.

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References

1. ↑ doi: https://dx.doi.org///doi.org/10.1016/j.cbi.2019.06.028