Structural dynamics of acetylcholinesterase and its implications in reactivators design

Abstract : Acetylcholinesterase (AChE), one of nature fastest enzyme, is the target of multiple toxics,including organophosphate nerve agents (OP). In the first part of this thesis I present thestructure-based development of a new uncharged reactivator, which showed characteristicsbetter than any molecule commercially available to date. The molecule has been rationallydesigned to present both affinity to the inhibited enzyme and good reactivation capabilities.The interactions between the lead molecule KM297 and AChE has been characterizedby means of flexible docking, molecular dynamics simulations and X-ray protein crystallography.The deeper understanding of its binding modes to both native and OP-inhibitedAChE has helped in developing a derivative, JDS207, whose binding mode at the peripheralsite of AChE is optimized. This derivative has also been studied by flexible docking and Xraycrystallography. The design of this family of reactivators taught us that a deep insightof the AChE dynamics is necessary to optimize ligands. The second part of the thesis isdevoted to the analysis of molecular dynamics simulations of AChE. At first, we assessedthat combining multiple short simulations is a fast and reliable method to characterizethe dynamics of the amino-acids side-chains. By comparing dynamics of the side-chainsfrom hAChE and TcAChE, we confirm that some key dynamical differences exist betweenthe two enzyme. The knowledge of the rotamers issued of MD simulation has lead us todevelop a new method to generate flexible receptors for docking, which is specific to eachsingle residue in the enzyme. This method has been validated by comparing its outputstructures with the ones found on the PDB database.
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Gianluca Santoni. Structural dynamics of acetylcholinesterase and its implications in reactivators design. Biomolecules [q-bio.BM]. Université Grenoble Alpes, 2015. English. ⟨NNT : 2015GREAY019⟩. ⟨tel-01212481⟩

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