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Targeting Acetylcholinesterase: Identification of Chemical Leads by High Throughput Screening, Structure Determination and Molecular Modeling
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, e26039Article in journal (Refereed) Published
Abstract [en]

Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e. g. in Alzheimer's disease), but may also act as dangerous toxins (e. g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685.mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.

Place, publisher, year, edition, pages
San Francisco: Public Library of Science , 2011. Vol. 6, no 11, e26039
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:umu:diva-52194DOI: 10.1371/journal.pone.0026039ISI: 000298168100002OAI: oai:DiVA.org:umu-52194DiVA: diva2:501736
Available from: 2012-02-14 Created: 2012-02-13 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase
Open this publication in new window or tab >>Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
En studie av icke-kovalenta interaktioner mellan läkemedelslika molekyler och proteinet acetylkolinesteras
Abstract [en]

The majority of drugs are small organic molecules, so-called ligands, that influence biochemical processes by interacting with proteins. The understanding of how and why they interact and form complexes is therefore a key component for elucidating the mechanism of action of drugs. The research presented in this thesis is based on studies of acetylcholinesterase (AChE). AChE is an essential enzyme with the important function of terminating neurotransmission at cholinergic synapses. AChE is also the target of a range of biologically active molecules including drugs, pesticides, and poisons. Due to the molecular and the functional characteristics of the enzyme, it offers both challenges and possibilities for investigating protein-ligand interactions. In the thesis, complexes between AChE and drug-like ligands have been studied in detail by a combination of experimental techniques and theoretical methods. The studies provided insight into the non-covalent interactions formed between AChE and ligands, where non-classical CH∙∙∙Y hydrogen bonds (Y = O or arene) were found to be common and important. The non-classical hydrogen bonds were characterized by density functional theory calculations that revealed features that may provide unexplored possibilities in for example structure-based design. Moreover, the study of two enantiomeric inhibitors of AChE provided important insight into the structural basis of enthalpy-entropy compensation. As part of the research, available computational methods have been evaluated and new approaches have been developed. This resulted in a methodology that allowed detailed analysis of the AChE-ligand complexes. Moreover, the methodology also proved to be a useful tool in the refinement of X-ray crystallographic data. This was demonstrated by the determination of a prereaction conformation of the complex between the nerve-agent antidote HI-6 and AChE inhibited by the nerve agent sarin. The structure of the ternary complex constitutes an important contribution of relevance for the design of new and improved drugs for treatment of nerve-agent poisoning. The research presented in the thesis has contributed to the knowledge of AChE and also has implications for drug discovery and the understanding of biochemical processes in general.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 76 p.
Keyword
acetylcholinesterase, drug discovery, density functional theory, hydrogen bond, nerve-agent antidote, non-covalent interaction, protein-ligand complex, structure-based design, thermodynamics, X-ray crystallography
National Category
Chemical Sciences
Research subject
läkemedelskemi
Identifiers
urn:nbn:se:umu:diva-129900 (URN)978-91-7601-644-2 (ISBN)
Public defence
2017-02-03, Stora hörsalen (KB.E3.03), KBC-huset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2017-01-13 Created: 2017-01-10 Last updated: 2017-01-13Bibliographically approved

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