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Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Molecular Biology - Medicinal Chemistry, University of Gothenburg.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå, Umeå University.
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2015 (English)In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 3, 199-215 p.Article in journal (Refereed) Published
Abstract [en]

Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

Place, publisher, year, edition, pages
2015. Vol. 29, no 3, 199-215 p.
Keyword [en]
Acetylcholinesterase, AChE, Quantitative structure-activity relationship, QSAR, Statistical molecular sign, SMD, Covariance matrix, Descriptors, Correlation
National Category
Medicinal Chemistry
URN: urn:nbn:se:umu:diva-101389DOI: 10.1007/s10822-014-9808-1ISI: 000349888300001PubMedID: 25351962OAI: diva2:840113
Available from: 2015-07-07 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Design strategies for new drugs targeting multicomponent systems: focusing on class II MHC proteins and acetylcholinesterase
Open this publication in new window or tab >>Design strategies for new drugs targeting multicomponent systems: focusing on class II MHC proteins and acetylcholinesterase
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Strategier för utveckling av nya läkemedel mot multikomponentsystem : fokus på klass II MHC proteiner och acetylkolinesteras
Abstract [en]

The field of medicinal chemistry is constantly evolving. Aided by advances within techniques as well as knowledge of biological systems, increasingly complex targets and drugs can be considered. This thesis includes two projects focusing on the design of drugs targeting multicomponent systems, referring to systems for which multiple components must be considered during the drug design process.

In the first project, the long-term goal is to develop a vaccine against the autoimmune disease rheumatoid arthritis (RA). The cause of RA is unknown, but it is genetically linked to expression of class II MHC proteins that present antigens to T-cell receptors (TCRs), responsible for initiating an immune response. A glycopeptide fragment, CII259–273, from type II collagen has shown promising results as a vaccine against arthritis resembling RA in mice. CII259–273 binds to the class II MHC protein followed by presentation to the TCR, forming a multicomponent system.

We have used molecular dynamics (MD) simulations to study the effect that modifications of CII259–273 have on the multicomponent system. Non-native amino acids and amide bond isosteres have been introduced. This has demonstrated the importance of retaining the backbone conformation of CII259–273, as well as the hydrogen bonds formed to the backbone. The ability to introduce such modifications would be of value to affect the potency towards the MHC protein, and prevent degradation of the glycopeptide. The studies have revealed a multicomponent system that is highly sensitive to even small modifications that can affect the dynamics of the entire complex.

In the second project, the long-term goal is to develop a broad-spectrum antidote against nerve agents. Nerve agents are extremely toxic compounds that act by covalently inhibiting the enzyme acetylcholinesterase (AChE), which is essential for termination of nerve signalling. A major limitation of current antidotes is that their efficiency is dependent on the type of nerve agent. A broad-spectrum antidote must be able to bind to the multicomponent system consisting of AChE covalently inhibited by different nerve agents. It will then act by performing a nucleophilic attack on the nerve agent adduct, thus breaking the covalent bond to AChE.

We have used statistical molecular design (SMD) and quantitative structure-activity relationship (QSAR) modelling to identify a fragment with a potency for AChE inhibited by different nerve agents. A nucleophilic component able to restore the enzyme to the active form was thereafter introduced. This resulted in a functional reactivator, efficient for multiple nerve agents. Furthermore, the mechanism of reactivation has been investigated through structural studies, enabled by a combination of X-ray crystallography and molecular modelling. A high flexibility of the reactivator, as well as the ability to bind to AChE in multiple conformations, are defined as important properties for a broad-spectrum antidote.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 92 p.
acetylcholinesterase, class II MHC protein, drug design, molecular dynamics simulation, multicomponent system, nerve agent, oxime, (quantitative) structure-activity relationship, reactivator, rheumatoid arthritis, statistical molecular design, T-cell receptor
National Category
Chemical Sciences
urn:nbn:se:umu:diva-137593 (URN)978-91-7601-737-1 (ISBN)
Public defence
2017-09-08, KB.E3.03 (stora hörsalen), KBC-huset, Umeå, 09:00 (English)
Available from: 2017-08-18 Created: 2017-08-14 Last updated: 2017-08-16Bibliographically approved

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