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  • 1. Allgardsson, Anders
    et al.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Akfur, Christine
    Worek, Franz
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id 1433Article in journal (Refereed)
    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.

  • 2.
    Andersson, C David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chen, Brian Y
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate assessment of virtual screening experiments2010In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 24, no 11-12, p. 757-767Article in journal (Refereed)
    Abstract [en]

    Discovering molecules with a desired biological function is one of the great challenges in drug research. To discover new lead molecules, virtual screens (VS) are often conducted, in which databases of molecules are screened for potential binders to a specific protein, using molecular docking. The choice of docking software and parameter settings within the software can significantly influence the outcome of a VS. In this study, we have applied chemometric methods such as design of experiments, principal component analysis and partial least-square projections to latent structure (PLS) to simulated VS experiments to find and compare suitable conditions for performing VS against six protein targets selected from the DUD databases. The docking parameters in FRED, and scoring functions in both FRED and GOLD docking software, were varied according to a statistical experimental design and a PLS model was calculated to correlate the experimental setup to the VS outcome. The study revealed that the choice of scoring function has the greatest influence on VS outcome, and that other parameters have varying influence, depending on the protein target. We also found that substantial bias can be introduced by the lack of variation of molecular properties in the databases used in the screening. Our results provide indications that docking experiments could be tailored to the protein target in order to obtain satisfactory VS results.

  • 3.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Nina
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Akfur, Christine
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Allgardsson, Anders
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Engdahl, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå (LCBU), Umeå University,.
    Ekström, Fredrik
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 19, p. 7615-7624Article in journal (Refereed)
    Abstract [en]

    The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.

  • 4.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hillgren, J. Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Molecular Biology - Medicinal Chemistry, University of Gothenburg.
    Lindgren, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå, Umeå University.
    Akfur, Christine
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase2015In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 3, p. 199-215Article in journal (Refereed)
    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.

  • 5.
    Andersson, C David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Ekblad, Torun
    Lindgren, Anders E G
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uciechowska, Urszula
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Niemiec, Moritz S
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Weigelt, Johan
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schüler, Herwig
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 17, p. 7706-7718Article in journal (Refereed)
    Abstract [en]

    The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.

  • 6.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Martinez, Nicolas
    Zeller, Dominik
    Allgardsson, Anders
    Koza, Michael M.
    Frick, Bernhard
    Ekström, Fredrik
    Peters, Judith
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering2018In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 36, p. 8516-8525Article in journal (Refereed)
    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.

  • 7.
    Andersson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Multivariate design of molecular docking experiments: An investigation of protein-ligand interactions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To be able to make informed descicions regarding the research of new drug molecules (ligands), it is crucial to have access to information regarding the chemical interaction between the drug and its biological target (protein). Computer-based methods have a given role in drug research today and, by using methods such as molecular docking, it is possible to investigate the way in which ligands and proteins interact. Despite the acceleration in computer power experienced in the last decades many problems persist in modelling these complicated interactions. The main objective of this thesis was to investigate and improve molecular modelling methods aimed to estimate protein-ligand binding. In order to do so, we have utilised chemometric tools, e.g. design of experiments (DoE) and principal component analysis (PCA), in the field of molecular modelling. More specifically, molecular docking was investigated as a tool for reproduction of ligand poses in protein 3D structures and for virtual screening. Adjustable parameters in two docking software were varied using DoE and parameter settings were identified which lead to improved results. In an additional study, we explored the nature of ligand-binding cavities in proteins since they are important factors in protein-ligand interactions, especially in the prediction of the function of newly found proteins. We developed a strategy, comprising a new set of descriptors and PCA, to map proteins based on their cavity physicochemical properties. Finally, we applied our developed strategies to design a set of glycopeptides which were used to study autoimmune arthritis. A combination of docking and statistical molecular design, synthesis and biological evaluation led to new binders for two different class II MHC proteins and recognition by a panel of T-cell hybridomas. New and interesting SAR conclusions could be drawn and the results will serve as a basis for selection of peptides to include in in vivo studies.

  • 8.
    Andersson, David C.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chen, Brian Y.
    Howard Hughes Institute, Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University..
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design of target-tailored virtual screening experimentsManuscript (preprint) (Other academic)
    Abstract [en]

    Discovering molecules with a desired biological function is one of the great challenges in drug research. To discover new lead molecules, in silico virtual screens (VS) are often conducted, in which databases of molecules are screened for potential binders to a specific protein, using molecular docking. The choice of docking software and parameter settings within the software can significantly influence the outcome of a VS. In this study, we have applied chemometric methods such as DoE, principal component analysis (PCA) and partial least-square projections to latent structure (PLS) to simulated VS experiments to find and compare suitable conditions for performing VS against six protein targets selected from the DUD databases. The docking parameters in FRED, and scoring functions in both FRED and GOLD docking software, were varied according to a statistical experimental design and a PLS model was calculated to correlate the experimental setup to the VS outcome. The study revealed that the choice of scoring function has the greatest influence on VS outcome, and that other parameters have varying influence, depending on the protein target. We also found that substantial bias can be introduced by the lack of variation of molecule properties in the databases used in the screening. The results indicate that docking experiments should be tailored to the protein target in order to obtain satisfactory VS results and that our methodology provides a suitable approach for such tailoring.

  • 9.
    Andersson, David C.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chen, Brian Y
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mapping of ligand-binding cavities in proteins2010In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 78, no 6, p. 1408-1422Article in journal (Refereed)
    Abstract [en]

    The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterize and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity, and charge). This approach can provide valuable information on the similarities and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterization and mapping of "orphan structures", selection of protein structures for docking studies in structure-based design, and identification of proteins for selectivity screens in drug design programs.

  • 10.
    Andersson, David C.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Martinez, N.
    Zeller, D.
    Rondahl, S. H.
    Koza, M. M.
    Frick, B.
    Ekstrom, F.
    Peters, J.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering2017In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 37, p. 25369-25379Article in journal (Refereed)
    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.

  • 11.
    Andersson, David C.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindström, Anton
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bylesjö, Max
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Raubacher, Florian
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A multivariate approach to investigate docking parameters' effects on docking performance2007In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 47, no 4, p. 1673-1687Article in journal (Refereed)
    Abstract [en]

    Increasingly powerful docking programs for analyzing and estimating the strength of protein-ligand interactions have been developed in recent decades, and they are now valuable tools in drug discovery. Software used to perform dockings relies on a number of parameters that affect various steps in the docking procedure. However, identifying the best choices of the settings for these parameters is often challenging. Therefore, the settings of the parameters are quite often left at their default values, even though scientists with long experience with a specific docking tool know that modifying certain parameters can improve the results. In the study presented here, we have used statistical experimental design and subsequent regression based on root-mean-square deviation values using partial least-square projections to latent structures (PLS) to scrutinize the effects of different parameters on the docking performance of two software packages: FRED and GOLD. Protein-ligand complexes with a high level of ligand diversity were selected from the PDBbind database for the study, using principal component analysis based on 1D and 2D descriptors, and space-filling design. The PLS models showed quantitative relationships between the docking parameters and the ability of the programs to reproduce the ligand crystallographic conformation. The PLS models also revealed which of the parameters and what parameter settings were important for the docking performance of the two programs. Furthermore, the variation in docking results obtained with specific parameter settings for different protein-ligand complexes in the diverse set examined indicates that there is great potential for optimizing the parameter settings for selected sets of proteins.

  • 12.
    Andersson, Ida E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Batsalova, Tsvetelina
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Dzhambazov, Balik
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Holmdahl, Rikard
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    AstraZeneca R&D Mölndal, Mölndal.
    Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e17881-Article in journal (Refereed)
    Abstract [en]

    The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.

  • 13.
    Berg, Lotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Artursson, Elisabet
    Hornberg, Andreas
    Tunemalm, Anna-Karin
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekstrom, Fredrik
    Targeting Acetylcholinesterase: Identification of Chemical Leads by High Throughput Screening, Structure Determination and Molecular Modeling2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, article id e26039Article in journal (Refereed)
    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.

  • 14.
    Berg, Lotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mishra, Brijesh Kumar
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes2016In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 8, p. 2672-2681Article in journal (Refereed)
    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.

  • 15.
    Berg, Lotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Niemiec, Moritz S.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Similar but Different: Thermodynamic and Structural Characterization of a Pair of Enantiomers Binding to Acetylcholinesterase2012In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 51, no 51, p. 12716-12720Article in journal (Refereed)
    Abstract [en]

    Take a closer look: Unexpectedly, a pair of enantiomeric ligands proved to have similar binding affinities for acetylcholinesterase. Further studies indicated that the enantiomers exhibit different thermodynamic profiles. Analyses of the noncovalent interactions in the protein-ligand complexes revealed that these differences are partly due to nonclassical hydrogen bonds between the ligands and aromatic side chains of the protein.

  • 16. Ekblad, Torun
    et al.
    Lindgren, Anders E. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Karlberg, Tobias
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schuler, Herwig
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Towards small molecule inhibitors of mono-ADP-ribosyltransferases2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 95, p. 546-551Article in journal (Refereed)
    Abstract [en]

    Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

  • 17. Horvath, Dragos
    et al.
    Lisurek, Michael
    Rupp, Bernd
    Kuehne, Ronald
    Specker, Edgar
    von Kries, Jens
    Rognan, Didier
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Enqvist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustavsson, Anna-Lena
    Remez, Nikita
    Mestres, Jordi
    Marcou, Gilles
    Varnek, Alexander
    Hibert, Marcel
    Quintana, Jordi
    Frank, Ronald
    Design of a general-purpose European compound screening library for EU-OPENSCREEN2014In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 9, no 10, p. 2309-2326Article in journal (Refereed)
    Abstract [en]

    This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target-or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.

  • 18. Karlberg, Tobias
    et al.
    Klepsch, Mirjam
    Thorsell, Ann-Gerd
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schuler, Herwig
    Structural Basis for Lack of ADP-ribosyltransferase Activity in Poly(ADP-ribose) Polymerase-13/Zinc Finger Antiviral Protein2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 12, p. 7336-7344Article in journal (Refereed)
    Abstract [en]

    Background: PARP13 contains a divergent PARP homology ADP-ribosyltransferase domain of unknown function. Results: The consensus NAD(+) pocket of PARP13 is occluded by interacting protein side chains. Conclusion: PARP13 lacks the structural requirements for NAD(+) binding. Significance: Evolutionary conservation of enzymatic inactivity suggests a need for a rigid domain structure.

    The mammalian poly(ADP-ribose) polymerase (PARP) family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. PARP13/ARTD13, also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. PARP13 features a divergent PARP homology domain missing a PARP consensus sequence motif; the domain has enigmatic functions and apparently lacks catalytic activity. We used x-ray crystallography, molecular dynamics simulations, and biochemical analyses to investigate the structural requirements for ADP-ribosyltransferase activity in human PARP13 and two of its functional partners in stress granules: PARP12/ARTD12, and PARP15/BAL3/ARTD7. The crystal structure of the PARP homology domain of PARP13 shows obstruction of the canonical active site, precluding NAD(+) binding. Molecular dynamics simulations indicate that this closed cleft conformation is maintained in solution. Introducing consensus side chains in PARP13 did not result in 3-aminobenzamide binding, but in further closure of the site. Three-dimensional alignment of the PARP homology domains of PARP13, PARP12, and PARP15 illustrates placement of PARP13 residues that deviate from the PARP family consensus. Introducing either one of two of these side chains into the corresponding positions in PARP15 abolished PARP15 ADP-ribosyltransferase activity. Taken together, our results show that PARP13 lacks the structural requirements for ADP-ribosyltransferase activity.

  • 19.
    Kauppi, Anna M.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Norberg, Henrik A.
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Sundin, Charlotta
    Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
    Linusson Jonsson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 6994-7011Article in journal (Other academic)
    Abstract [en]

    Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.

  • 20.
    Larsson, Malin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fraccalvieri, Domenico
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bonati, Laura
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals2018In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 25, no 3, p. 2436-2449Article in journal (Refereed)
    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.

  • 21.
    Lindgren, Anders E. G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Ekblad, Torun
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thorsell, Ann-Gerd
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nhan, Ton Tong
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hellsten, Victor
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Weigelt, Johan
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schuler, Herwig
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP32013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 23, p. 9556-9568Article in journal (Refereed)
    Abstract [en]

    The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

  • 22.
    Lindgren, Anders E. G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlberg, Tobias
    Thorsell, Ann-Gerd
    Hesse, Mareike
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekblad, Torun
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pinto, Ana Filipa
    Weigelt, Johan
    Hottiger, Michael O.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schueler, Herwig
    PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP32013In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 8, p. 1698-1703Article in journal (Refereed)
    Abstract [en]

    Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

  • 23.
    Lindgren, Cecilia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Nina
    Swedish Defence Research Agency, CBRN Defence and Security.
    Akfur, Christine
    Swedish Defence Research Agency, CBRN Defence and Security.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hillgren, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Worek, Franz
    Ekström, Fredrik
    Swedish Defence Research Agency, CBRN Defence and Security.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design of Reactive Drugs: Structure and Mechanism of Novel Nerve Agent AntidotesManuscript (preprint) (Other academic)
  • 24.
    Lindström, Anton
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Adam
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bone contrast optimization in magnetic resonance imaging using experimental design of ultra-short echo-time parameters2013In: Chemometrics and Intelligent Laboratory Systems, ISSN 0169-7439, E-ISSN 1873-3239, Vol. 125, p. 33-39Article in journal (Refereed)
    Abstract [en]

    For the purpose of improved planning and treatment by radiation of tumours, we present work exploring the effect of controllable ultra-short echo-time (UTE) sequence settings on the bone contrast in magnetic resonance (MR) imaging, using design of experiments (DoE). Images were collected using UTE sequences from MR imaging and from standard computed tomography (CT). CT was used for determining the spatial position of the bony structures in an animal sample and co-registered with the MR images. The effect of the UTE sequence parameter flip angle (Flip), repetition time (T-R), echo time (T-E), image matrix size (Vox) and number of radial sampling spokes (Samp) were studied. The parameters were also investigated in a healthy voluntary and it was determined that the optimal UTE settings for high bone contrast in a clinically relevant set up were: Flip similar to 9 degrees and T-E = 0.07 ms, while T-R was kept at 8 ms, Vox at 192 and Samp at 30,000. The use of response surface maps, describing the modelled relation between bone contrast and UTE settings, founded in the DoE, may provide information and be a tool to more appropriately select suitable UTE sequence settings.

  • 25.
    Lindström, Anton
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Edvinsson, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Ida E
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Raubacher, Florian
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Postprocessing of docked protein-ligand complexes using implicit solvation models2011In: Journal of chemical information and modeling, ISSN 1549-960X (online), 1549-9596 (print), Vol. 51, no 2, p. 267-282Article in journal (Refereed)
    Abstract [en]

    Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein−ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson−Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein−ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GBHCT+SA model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) Aq protein. These results indicate that the protocol for the postprocessing of docked protein−ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery.

  • 26.
    Mojica, Sergio A.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Salin, Olli
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bastidas, Robert J.
    Sunduru, Naresh
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Núñez-Otero, Carlos
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Valdivia, Raphael H.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 10, article id e00716-17Article in journal (Refereed)
    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.

  • 27.
    Palm-Espling, Maria
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Björn, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Determinants for simultaneous binding of copper and platinum to human chaperone Atox1: hitchhiking not hijacking2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, article id e70473Article in journal (Refereed)
    Abstract [en]

    Cisplatin (CisPt) is an anticancer agent that has been used for decades to treat a variety of cancers. CisPt treatment causes many side effects due to interactions with proteins that detoxify the drug before reaching the DNA. One key player in CisPt resistance is the cellular copper-transport system involving the uptake protein Ctr1, the cytoplasmic chaperone Atox1 and the secretory path ATP7A/B proteins. CisPt has been shown to bind to ATP7B, resulting in vesicle sequestering of the drug. In addition, we and others showed that the apo-form of Atox1 could interact with CisPt in vitro and in vivo. Since the function of Atox1 is to transport copper (Cu) ions, it is important to assess how CisPt binding depends on Cu-loading of Atox1. Surprisingly, we recently found that CisPt interacted with Cu-loaded Atox1 in vitro at a position near the Cu site such that unique spectroscopic features appeared. Here, we identify the binding site for CisPt in the Cu-loaded form of Atox1 using strategic variants and a combination of spectroscopic and chromatographic methods. We directly prove that both metals can bind simultaneously and that the unique spectroscopic signals originate from an Atox1 monomer species. Both Cys in the Cu-site (Cys12, Cys15) are needed to form the di-metal complex, but not Cys41. Removing Met10 in the conserved metal-binding motif makes the loop more floppy and, despite metal binding, there are no metal-metal electronic transitions. In silico geometry minimizations provide an energetically favorable model of a tentative ternary Cu-Pt-Atox1 complex. Finally, we demonstrate that Atox1 can deliver CisPt to the fourth metal binding domain 4 of ATP7B (WD4), indicative of a possible drug detoxification mechanism.

  • 28.
    Qin, Liena
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vo, Duc-Duy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nakhai, Azadeh
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Diversity-Oriented Synthesis of Libraries Based on Benzofuran and 2,3-Dihydrobenzofuran Scaffolds2017In: ACS Combinatorial Science, ISSN 2156-8952, Vol. 19, no 6, p. 370-376Article in journal (Refereed)
    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.

  • 29.
    Rogne, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer-Eriksson, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nucleation of an Activating Conformational Change by a Cation−Π Interaction2019In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 58, no 32, p. 3408-3412Article in journal (Refereed)
    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.

  • 30.
    Saleeb, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mojica, Sergio
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Anna U.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis2018In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 1077-1089Article in journal (Refereed)
    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.

  • 31.
    Sun, Kun
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bröms, Jeanette
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gurram, Bharat Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 7, p. 4123-4130Article in journal (Refereed)
    Abstract [en]

    The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an alpha-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A(1) activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.

  • 32.
    Sunduru, Naresh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Marwaha, Sania
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors2017In: 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)
    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.

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