Acetylcholinesterase: Molecular Modeling with the Whole Toolkit

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 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-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.

Chemical and biological insights on Cotoneaster integerrimus: A new (-)- epicatechin source for food and medicinal applications

“…The grid for docking was generated by Autodock tools (ADT) (Sanner, 1999) by centring the grid on the co-crystallized inhibitor present in the crystal structures downloaded. Only in the case of acetylcholinesterase, the binding pocket was centred around the residues His447, covering all the residues reported in literature to be part of the enzymatic pocket: Ser203, Glu334, Tyr124, Trp286, Tyr341, Asp74 (Lushington et al, 2006). The rotable bonds of (-)-epicatechin were selected by default.…”

<i>In silico</i> design and evaluation of carboxylesterase inhibitors

“…3), so determining which structure the known inhibitors are binding to is complicated. The basic rationale for the need to include molecular dynamics in the development of enzyme inhibitors for the related AChE has been recently reviewed 33) . This rationale also applies to CEs.…”

“…Generic docking of known AChE inhibitors to a static AChE are generally not predictive for the relative magnitudes of the inhibition constants 33) . This has been attributed to the inability of static models to correctly calculate the entropy change upon inhibitor binding.…”

Global and local molecular dynamics of a bacterial carboxylesterase provide insight into its catalytic mechanism

“…The use of MD in the development of enzyme inhibitors for the related α/β hydrolase acetylcholinesterase (AChE) has been recently reviewed [17] and these principles also apply to CEs. Briefly, enzymes are in constant motion at temperatures near 37°C and the understanding of the fluctuation is crucial for understanding of the interactions of the enzyme with its substrate or inhibitors.…”

“…Acetylcholinesterase has been the subject of considerable MD simulation for the reasons given above (reviewed in [17, 19]). In contrast, only a few studies of the MD of CEs have been reported [16, 20, 21].…”