Abstract
Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last decade, largely because of the systems importance to medical conditions such as myasthenia gravis, Alzheimers disease and Parkinsons 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-tiered pharmaceutical 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.
Keywords: Acetylcholinesterase, Alzheimer's disease, organophosphorus nerve agents, molecular docking, molecular dynamics, quantum chemistry, QSAR, COMBINE
Current Topics in Medicinal Chemistry
Title: Acetylcholinesterase: Molecular Modeling with the Whole Toolkit
Volume: 6 Issue: 1
Author(s): Gerald H. Lushington, Jian-Xin Guo and Margaret M. Hurley
Affiliation:
Keywords: Acetylcholinesterase, Alzheimer's disease, organophosphorus nerve agents, molecular docking, molecular dynamics, quantum chemistry, QSAR, COMBINE
Abstract: Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last decade, largely because of the systems importance to medical conditions such as myasthenia gravis, Alzheimers disease and Parkinsons 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-tiered pharmaceutical 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.
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Cite this article as:
Lushington H. Gerald, Guo Jian-Xin and Hurley M. Margaret, Acetylcholinesterase: Molecular Modeling with the Whole Toolkit, Current Topics in Medicinal Chemistry 2006; 6 (1) . https://dx.doi.org/10.2174/156802606775193293
DOI https://dx.doi.org/10.2174/156802606775193293 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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