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Rogne, P., Andersson, D., Grundström, C., Sauer-Eriksson, E., Linusson, A. & Wolf-Watz, M. (2019). Nucleation of an Activating Conformational Change by a Cation−Π Interaction. Biochemistry, 58(32), 3408-3412
Open this publication in new window or tab >>Nucleation of an Activating Conformational Change by a Cation−Π Interaction
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2019 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 58, no 32, p. 3408-3412Article in journal (Refereed) Published
Abstract [en]

As a key molecule in biology, adenosine triphosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and cofactor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation−π interaction. In addition to recognition, the interaction was found to have dual functionality. First, it nucleates the activating conformational transition of the ATP binding domain and also affects the specificity in the distant AMP binding domain. In light of the functional consequences resulting from the cation−π interaction, it is possible that the mode of ATP recognition may be a useful tool in enzyme design.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-162099 (URN)10.1021/acs.biochem.9b00538 (DOI)000480827100002 ()31339702 (PubMedID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-09-02Bibliographically approved
Lindgren, C., Tyagi, M., Viljanen, J., Toms, J., Ge, C., Zhang, N., . . . Linusson, A. (2018). Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis. Journal of Medicinal Chemistry, 61(11), 4774-4790
Open this publication in new window or tab >>Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 11, p. 4774-4790Article in journal (Refereed) Published
Abstract [en]

Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-150782 (URN)10.1021/acs.jmedchem.7b01880 (DOI)000435613100008 ()29727183 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved
Larsson, M., Fraccalvieri, D., Andersson, C. D., Bonati, L., Linusson, A. & Andersson, P. L. (2018). Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals. Environmental science and pollution research international, 25(3), 2436-2449
Open this publication in new window or tab >>Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals
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2018 (English)In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 25, no 3, p. 2436-2449Article in journal (Refereed) Published
Abstract [en]

We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like compounds, which is related to these compounds’ potential to induce cancer and a wide range of endocrine and immune system related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by three enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6,445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-p-hydroxyanilino-carbazole, and 3-(2-chloro-4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
virtual screening, aryl hydrocarbon receptor, industrial chemicals, molecular descriptors, structural similarity, molecular docking
National Category
Chemical Sciences Environmental Sciences
Identifiers
urn:nbn:se:umu:diva-139486 (URN)10.1007/s11356-017-0437-9 (DOI)000422970600042 ()29127629 (PubMedID)
Note

Originally included in thesis in manuscript form

Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2018-06-09Bibliographically approved
Andersson, C. D., Martinez, N., Zeller, D., Allgardsson, A., Koza, M. M., Frick, B., . . . Linusson, A. (2018). Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering. Journal of Physical Chemistry B, 122(36), 8516-8525
Open this publication in new window or tab >>Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering
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2018 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 36, p. 8516-8525Article in journal (Refereed) Published
Abstract [en]

The enzyme acetylcholinesterase (AChE) is essential in humans and animals because it catalyzes the breakdown of the nerve-signaling substance acetylcholine. Small molecules that inhibit the function of AChE are important for their use as drugs in the, for example, symptomatic treatment of Alzheimer's disease. New and improved inhibitors are warranted, mainly because of severe side effects of current drugs. In the present study, we have investigated if and how two enantiomeric inhibitors of AChE influence the overall dynamics of noncovalent complexes, using elastic incoherent neutron scattering. A fruitful combination of univariate models, including a newly developed non-Gaussian model for atomic fluctuations, and multivariate methods (principal component analysis and discriminant analysis) was crucial to analyze the fine details of the data. The study revealed a small but clear increase in the dynamics of the inhibited enzyme compared to that of the noninhibited enzyme and contributed to the fundamental knowledge of the mechanisms of AChE-inhibitor binding valuable for the future development of inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-152405 (URN)10.1021/acs.jpcb.8b05485 (DOI)000444922800003 ()30110543 (PubMedID)
Funder
Swedish Research Council, 2014-4675
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-05Bibliographically approved
Knutsson, S., Engdahl, C., Kumari, R., Forsgren, N., Lindgren, C., Kindahl, T., . . . Linusson, A. (2018). Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency. Journal of Medicinal Chemistry, 61(23), 10545-10557
Open this publication in new window or tab >>Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 23, p. 10545-10557Article in journal (Refereed) Published
Abstract [en]

Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-154812 (URN)10.1021/acs.jmedchem.8b01060 (DOI)000453488200014 ()30339371 (PubMedID)
Funder
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Veenaas, C., Linusson, A. & Haglund, P. (2018). Retention-time prediction in comprehensive two-dimensional gas chromatography to aid identification of unknown contaminants. Analytical and Bioanalytical Chemistry, 410(30), 7931-7941
Open this publication in new window or tab >>Retention-time prediction in comprehensive two-dimensional gas chromatography to aid identification of unknown contaminants
2018 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 410, no 30, p. 7931-7941Article in journal (Refereed) Published
Abstract [en]

Comprehensive two-dimensional (2D) gas chromatography (GC×GC) coupled to mass spectrometry (MS, GC×GC-MS), which enhances selectivity compared to GC-MS analysis, can be used for non-directed analysis (non-target screening) of environmental samples. Additional tools that aid in identifying unknown compounds are needed to handle the large amount of data generated. These tools include retention indices for characterizing relative retention of compounds and prediction of such. In this study, two quantitative structure–retention relationship (QSRR) approaches for prediction of retention times (1tR and 2tR) and indices (linear retention indices (LRIs) and a new polyethylene glycol–based retention index (PEG-2I)) in GC × GC were explored, and their predictive power compared. In the first method, molecular descriptors combined with partial least squares (PLS) analysis were used to predict times and indices. In the second method, the commercial software package ChromGenius (ACD/Labs), based on a “federation of local models,” was employed. Overall, the PLS approach exhibited better accuracy than the ChromGenius approach. Although average errors for the LRI prediction via ChromGenius were slightly lower, PLS was superior in all other cases. The average deviations between the predicted and the experimental value were 5% and 3% for the 1tR and LRI, and 5% and 12% for the 2tR and PEG-2I, respectively. These results are comparable to or better than those reported in previous studies. Finally, the developed model was successfully applied to an independent dataset and led to the discovery of 12 wrongly assigned compounds. The results of the present work represent the first-ever prediction of the PEG-2I.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
GCxGC, Retention-time prediction, Partial least squares (PLS), Federation of local models, Quantitative structure-retention relationship (QSRR), Non-target analysis
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:umu:diva-154932 (URN)10.1007/s00216-018-1415-x (DOI)000450071400011 ()30361914 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-04-09Bibliographically approved
Allgardsson, A., Andersson, C. D., Akfur, C., Worek, F., Linusson, A. & Ekström, F. (2017). An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet. Molecules, 22(9), Article ID 1433.
Open this publication in new window or tab >>An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet
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2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id 1433Article in journal (Refereed) Published
Abstract [en]

Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.

Place, publisher, year, edition, pages
MDPI AG, 2017
Keywords
cholinesterase, acetylcholinesterase, cooperativity, crystal violet, Hill coefficient, new modality, non-bonded bivalence
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-140654 (URN)10.3390/molecules22091433 (DOI)000411499400040 ()
Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2018-06-09Bibliographically approved
Andersson, D. C., Martinez, N., Zeller, D., Rondahl, S. H., Koza, M. M., Frick, B., . . . Linusson, A. (2017). Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering. Physical Chemistry, Chemical Physics - PCCP, 19(37), 25369-25379
Open this publication in new window or tab >>Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering
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2017 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 37, p. 25369-25379Article in journal (Refereed) Published
Abstract [en]

An essential role of enzymes is to catalyze various chemical reactions in the human body and inhibition of the enzymatic activity by small molecules is the mechanism of action of many drugs or tool compounds used to study biological processes. Here, we investigate the effect on the dynamics of the serine protease alpha-chymotrypsin when in complex with two different covalently bound inhibitors using elastic incoherent neutron scattering. The results show that the inhibited enzyme displays enhanced dynamics compared to the free form. The difference was prominent at higher temperatures (240-310 K) and the type of motions that differ include both small amplitude motions, such as hydrogen atom rotations around a methyl group, and large amplitude motions, such as amino acid side chain movements. The measurements were analyzed with multivariate methods in addition to the standard univariate methods, allowing for a more in-depth analysis of the types of motions that differ between the two forms. The binding strength of an inhibitor is linked to the changes in dynamics occurring during the inhibitor-enzyme binding event and thus these results may aid in the deconvolution of this fundamental event and in the design of new inhibitors.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2017
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-140878 (URN)10.1039/c7cp04041e (DOI)000412271600015 ()28894859 (PubMedID)
Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2018-06-09Bibliographically approved
Knutsson, S., Kindahl, T., Engdahl, C., Nikjoo, D., Forsgren, N., Kitur, S., . . . Linusson, A. (2017). N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes. European Journal of Medicinal Chemistry, 134, 415-427
Open this publication in new window or tab >>N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
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2017 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 134, p. 415-427Article in journal (Refereed) Published
Abstract [en]

Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.

Keywords
Acetylcholinesterase 1, Aedes aegypti, Anopheles gambiae, Insecticides, Thiourea, Vector control
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-134612 (URN)10.1016/j.ejmech.2017.03.050 (DOI)000401677500035 ()28433681 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-06-09Bibliographically approved
Engdahl, C., Knutsson, S., Ekström, F. & Linusson, A. (2016). Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes. Journal of Medicinal Chemistry, 59(20), 9409-9421
Open this publication in new window or tab >>Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 20, p. 9409-9421Article in journal (Other academic) Published
Abstract [en]

Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-119925 (URN)10.1021/acs.jmedchem.6b00967 (DOI)000386641300010 ()
Note

Originally included in thesis in manuscript form.

Available from: 2016-05-03 Created: 2016-05-02 Last updated: 2018-06-25Bibliographically approved
Projects
Probing molecular interactions of protein-ligand complexes guided by an integration of chemometrics and molecular modelling [2008-03672_VR]; Umeå UniversityProbing Non-Covalent Interactions in Protein-Ligand Complexes [2011-04840_VR]; Umeå UniversityVector Control by Multiple Classes of Small Organic Compounds to Combat Mosquito-Borne Infectious Diseases and Suppress Insecticide Resistance [2014-02636_VR]; Umeå UniversityVector Control by Multiple Classes of Small Organic Compounds to Combat Mosquito-Borne Infectious Diseases and Suppress Insecticide Resistance [2014-04218_VR]; Umeå UniversityTargeting Fundamental Aspects of Protein-Ligand Interactions to Improve Computer-Aided Molecular Design [2014-04675_VR]; Umeå UniversityNew insecticides for sustainable and effective vector control of disease-transmitting mosquitoes [2017-00664_VR]; Umeå UniversityElucidating the Mechanism of Therapeutic Antidotes for Neurotoxicity caused by Nerve Agents and Pesticides [2018-05176_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0063-8912

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