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 three-dimensional structures of mouse and Torpedo californica
acetylcholinesterase are very similar, 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.
References
- ↑ REF
