Acetylcholinesterase Reprised: Molecular Modeling with the Whole Toolkit

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Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last 15 years, largely due to the system's importance to medical conditions such as myasthenia gravis, Alzheimer's disease and Parkinson's disease, and well as its famous toxicological susceptibility to nerve agents. The complexity inherent in such a system with multiple complementary binding sites, critical dynamic effects and intricate mechanisms for enzymatic function and covalent inhibition, has led to an impressively diverse selection of simulation techniques being applied to the system, including quantum chemical mechanistic studies, molecular docking prediction of noncovalent complexes and their associated binding free energies, molecular dynamics conformational analysis and transport kinetics prediction, and quantitative structure activity relationship modeling to tie salient details together into a coherent predictive tool. Effective drug and prophylaxis design strategies for a complex target like this requires some understanding and appreciation for all of the above methods, thus it makes an excellent case study for multi-faceted pharmacological modeling. This paper reviews a sample of the more important studies on acetylcholinesterase and helps to elucidate their interdependencies. Potential future directions are introduced based on the special methodological needs of the acetylcholinesterase system and on emerging trends in molecular modeling.