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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
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
Saleeb, M., Mojica, S., Eriksson, A. U., Andersson, C. D., Gylfe, Å. & Elofsson, M. (2018). Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis. European Journal of Medicinal Chemistry, 143, 1077-1089
Open this publication in new window or tab >>Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 1077-1089Article in journal (Refereed) Published
Abstract [en]

A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
2, 3-diaryl-2, 3-dihydrobenzofuran, 2, 3-diaryl-benzofuran, Antibacterial, Benzofuran, Chlamydia
National Category
Organic Chemistry Biological Sciences
Identifiers
urn:nbn:se:umu:diva-143062 (URN)10.1016/j.ejmech.2017.11.099 (DOI)000428216700089 ()29232584 (PubMedID)
Funder
Swedish Foundation for Strategic Research , SB12-0022Swedish Research Council, 621-2014-4670
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-08-24Bibliographically 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
Qin, L., Vo, D.-D., Nakhai, A., Andersson, C. D. & Elofsson, M. (2017). Diversity-Oriented Synthesis of Libraries Based on Benzofuran and 2,3-Dihydrobenzofuran Scaffolds. ACS Combinatorial Science, 19(6), 370-376
Open this publication in new window or tab >>Diversity-Oriented Synthesis of Libraries Based on Benzofuran and 2,3-Dihydrobenzofuran Scaffolds
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2017 (English)In: ACS Combinatorial Science, ISSN 2156-8952, Vol. 19, no 6, p. 370-376Article in journal (Refereed) Published
Abstract [en]

Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1.9-4.7.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
Keywords
diversity oriented synthesis, benzofuran, 2, 3-dihydrobenzofuran
National Category
Chemical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-137641 (URN)10.1021/acscombsci.7b00014 (DOI)000403387200004 ()28306238 (PubMedID)
Available from: 2017-07-13 Created: 2017-07-13 Last updated: 2018-06-09Bibliographically approved
Mojica, S. A., Salin, O., Bastidas, R. J., Sunduru, N., Hedenström, M., Andersson, C. D., . . . Gylfe, Å. (2017). N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF. Antimicrobial Agents and Chemotherapy, 61(10), Article ID e00716-17.
Open this publication in new window or tab >>N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 10, article id e00716-17Article in journal (Refereed) Published
Abstract [en]

The type II fatty acid synthesis (FASII) pathway is essential for bacterial lipid biosynthesis and continues to be a promising target for novel antibacterial compounds. Recently, it has been demonstrated that Chlamydia is capable of FASII and this pathway is indispensable for Chlamydia growth. Previously, a high-content screen with Chlamydia trachomatis-infected cells was performed, and acylated sulfonamides were identified to be potent growth inhibitors of the bacteria. C. trachomatis strains resistant to acylated sulfonamides were isolated by serial passage of a wild-type strain in the presence of low compound concentrations. Results from whole-genome sequencing of 10 isolates from two independent drug-resistant populations revealed that mutations that accumulated in fabF were predominant. Studies of the interaction between the FabF protein and small molecules showed that acylated sulfonamides directly bind to recombinant FabF in vitro and treatment of C. trachomatis-infected HeLa cells with the compounds leads to a decrease in the synthesis of Chlamydia fatty acids. This work demonstrates the importance of FASII for Chlamydia development and may lead to the development of new antimicrobials.

Place, publisher, year, edition, pages
American society for microbiology, 2017
Keywords
Chlamydia trachomatis, FAS, antimicrobial agents, drug targets
National Category
Microbiology Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-140637 (URN)10.1128/AAC.00716-17 (DOI)000411481800016 ()
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2018-06-09Bibliographically approved
Sunduru, N., Svensson, M., Cipriano, M., Marwaha, S., Andersson, D. C., Svensson, R., . . . Elofsson, M. (2017). N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors. Journal of enzyme inhibition and medicinal chemistry (Print), 32(1), 513-521
Open this publication in new window or tab >>N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors
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2017 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 32, no 1, p. 513-521Article in journal (Refereed) Published
Abstract [en]

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b] pyri-din-2-yl) phenyl) acetamide, 4g, with an IC50 of 2.6 mu M as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b] pyridin-2-yl)phenyl) acetamide, 4i, with an IC50 of 0.35 mu M.

Keywords
Fatty acid amide hydrolase inhibitors, endocannabinoid system, oxazolo[4, 5-b]pyridine anilines, 1H- idazo[4, 5-b]pyridine anilines
National Category
Medicinal Chemistry Neurosciences
Identifiers
urn:nbn:se:umu:diva-131874 (URN)10.1080/14756366.2016.1265520 (DOI)000392591100045 ()28114819 (PubMedID)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-06-09Bibliographically approved
Berg, L., Mishra, B. K., Andersson, C. D., Ekström, F. & Linusson, A. (2016). The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes. Chemistry - A European Journal, 22(8), 2672-2681
Open this publication in new window or tab >>The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 8, p. 2672-2681Article in journal (Refereed) Published
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
Keywords
acetylcholinesterase, density functional calculations, drug design, hydrogen bonds, quantum chemistry
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-118248 (URN)10.1002/chem.201503973 (DOI)000370193000017 ()26751405 (PubMedID)
Available from: 2016-03-16 Created: 2016-03-14 Last updated: 2018-06-07Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8198-1688

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