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The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 8, 2672-2681 p.Article in journal (Refereed) Published
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Text
Abstract [en]

Molecular recognition events in biological systems are driven by non-covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CHY type involving electron-deficient CH donors using dispersion-corrected density functional theory (DFT) calculations applied to acetylcholinesterase-ligand complexes. The strengths of CHY interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non-activated CHY interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CHY interactions when analysing protein-ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2016. Vol. 22, no 8, 2672-2681 p.
Keyword [en]
acetylcholinesterase, density functional calculations, drug design, hydrogen bonds, quantum chemistry
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-118248DOI: 10.1002/chem.201503973ISI: 000370193000017PubMedID: 26751405OAI: oai:DiVA.org:umu-118248DiVA: diva2:912496
Available from: 2016-03-16 Created: 2016-03-14 Last updated: 2017-01-11Bibliographically 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)
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Available from: 2017-01-13 Created: 2017-01-10 Last updated: 2017-01-13Bibliographically approved

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