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Search: WFRF:(Andersson Mikael) > Andersson David

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1.
  • Andersson, C. David, et al. (author)
  • Benefits of statistical molecular design, covariance analysis, and reference models in QSAR : a case study on acetylcholinesterase
  • 2015
  • In: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 29:3, s. 199-215
  • Journal article (peer-reviewed)abstract
    • 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.
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2.
  • Andersson, C David, et al. (author)
  • Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
  • 2012
  • In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:17, s. 7706-7718
  • Journal article (peer-reviewed)abstract
    • 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.
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3.
  • Andersson, David, et al. (author)
  • Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists.
  • 2002
  • In: Molecular Pharmacology. - 1521-0111. ; 62:3, s. 705-713
  • Journal article (peer-reviewed)abstract
    • Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.
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4.
  • Ekblad, Torun, et al. (author)
  • Towards small molecule inhibitors of mono-ADP-ribosyltransferases
  • 2015
  • In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 95, s. 546-551
  • Journal article (peer-reviewed)abstract
    • 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.
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5.
  • Horvath, Dragos, et al. (author)
  • Design of a general-purpose European compound screening library for EU-OPENSCREEN
  • 2014
  • In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 9:10, s. 2309-2326
  • Journal article (peer-reviewed)abstract
    • 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.
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7.
  • Johansson, Emil, 1985-, et al. (author)
  • Exploring the effect of structure-based scaffold hopping on the inhibition of coxsackievirus a24v transduction by pentavalent n-acetylneuraminic acid conjugates
  • 2021
  • In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:16
  • Journal article (peer-reviewed)abstract
    • Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.
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8.
  • Johansson, Emil, et al. (author)
  • Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections
  • 2020
  • In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 15:10, s. 2683-2691
  • Journal article (peer-reviewed)abstract
    • Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.
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9.
  • Kauppi, Anna M., 1971-, et al. (author)
  • Inhibitors of type III secretion in Yersinia : design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides
  • 2007
  • In: Bioorganic & Medicinal Chemistry. - : Elsevier Ltd. - 0968-0896 .- 1464-3391. ; 15:22, s. 6994-7011
  • Journal article (other academic/artistic)abstract
    • 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.
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10.
  • Levin, Lars-Åke, et al. (author)
  • Styrformer för effektiv läkemedelsanvändning
  • 2010
  • Reports (other academic/artistic)abstract
    • Rapporten Styrformer för effektiv läkemedelsanvändning har tagits fram av Institutionen för medicin och hälsa vid Linköpings universitet. Utgångspunkten var ett uppdrag som givits av Socialdepartementet och Sveriges kommuner och landsting inom arbetet med Handlingsplan för effektivare läkemedelsanvändning. Handlingsplanen presenterades av en arbetsgrupp i mars 2009. Rapportens resultat kommer att integreras i arbetet med en nationell läkemedelsstrategi.Syftet med rapporten är att kartlägga olika styrformer för läkemedelsanvändning i landstingen och analysera deras betydelse för rättvisa och effektivitet i läkemedelsanvändningen. Ett delsyfte med studien, som görs för första gången, är att starta utvecklingen av metodik för den här typen av analys.Studien består av tre delar. Den första delen är en kartläggning av landstingens styrning av läkemedelsförmånerna. I del två redovisas mått (indikatorer) som beskriver utfallet i form av läkemedelsanvändningen i olika landsting. I del tre analyseras skillnader i kunskaps- och ekonomistyrning i relation till skillnader i läkemedelsanvändning i form av de utfallsmått som beskrivits i del två.Material till kartläggningen har insamlats via enkät till samtliga 21 landsting och enkätsvaren har sedan följts upp per telefon. I enkäten efterfrågades hur styrningen fungerade år 2008 och år 2005.Decentraliseringsgraden i landstingen har ökat. Kostnadsansvaret låg på klinik- och vårdcentralsnivå i tolv landsting (9 landsting år 2005), på en mellannivå i fem landsting (7 landsting år 2005) och centralt i fyra landsting år 2008 (5 landsting år 2005).Fler landsting valde en förskrivarbaserad modell (9 landsting) istället för en befolkningsbaserad modell (8 landsting) 2008. Tre år tidigare var det istället något fler som hade valt den befolkningsbaserade modellen (10 landsting respektive 6 landsting med förskrivarbaserad modell).Tio landsting hade en integrerad hälso- och sjukvårdsbudget år 2008 (8 landsting 2005). Sju landsting hade en separat läkemedelsbudget (8 landsting 2005).Oavsett om landstingen hade en separat läkemedelsbudget eller en integrerad hälso- och sjukvårdsbudget var det vanligast att över- och underskott på lokal nivå hanterades inom den totala budgetramen för hälso- och sjukvård. Några landsting hade utvecklat olika incitamentsmodeller där det fanns möjlighet att ta del av hela eller delar av eventuellt överskott om vissa förskrivningsmål/produktionsmål/ kvalitetsmål uppfylldes.Frågan om hur under- och överskott hanteras i praktiken upplevdes som svår att besvara av kontaktpersonerna. Det finns en osäkerhet om vilka formella regler som egentligen gäller, vilket påverkat svaren.Kunskapsstöd i form av läkemedelskommitténs rekommendationslista och producentobunden information fanns i alla landsting. Representanter för ansåg generellt att deras olika former av förskrivarstöd fungerade minst lika bra som motsvarande stöd i övriga landsting. Ett undantag var IT-baserat förskrivarstöd inom privat vård där många landsting ansåg att det egna stödet fungerade sämre än i andra landsting.Vid en rangordning av de tre viktigaste stödformerna anses IT-baserat förskrivarstöd vid sjukhus som allra viktigast följt av läkemedelskommitténs rekommendationslista samt producentobundeninformation.Tidigare kartläggningar visar att landstingen över tiden hanterat kostnadsansvaret för öppenvårdsläkemedel på olika sätt. Jämfört med en tidigare undersökning från 2002 har decentraliseringsgraden inomlandstingen år 2008 ökat markant[1, 2].Analysdelen – med sammanvägning av enkätresultat och utfall av indikatorer i skilda dimensioner – visar att:Landstingens struktur i form av förekomst av universitet och landstingets storlek är den faktor som påverkar läkemedelsanvändningen mest.Landsting som infört ett decentraliserat kostnadsansvar jämfört med övriga landsting:har inte mindre volym (DDD/invånare) men lägre kostnad per invånare.har bättre följsamhet till läkemedel som rekommenderas av läkemedelskommittéer.avvek däremot inte från övriga landsting vad gällde andel patienter som fick kostnadseffektiv behandling, olämplig förskrivning inklusive polyfarmaci, användning av nya läkemedel med stor innovationshöjd samt jämlikhet. Detta kan eventuellt förklaras av otillräcklig statistisk styrka för att finna skillnader mellan grupperna.Kunskapsstyrning har i denna studie en liten påverkan på  läkemedelsanvändningen. Det beror bland annat på att:kunskapsstyrning är starkt korrelerad med struktur vilket gör analysen svårtolkad.kunskapsstyrning är svår att operationalisera och mäta.kunskapsvariablernas variation är dessutom liten mellan landstingen.IT-stöd i form av gemensam läkemedelslista samvarierar emellertid med kvalitetsvariabeln ”färre interaktioner”.Ett huvudresultat är att landsting med ett decentraliserat kostnadsansvar för läkemedel samtidigt hade lägre kostnader för läkemedel i öppen vård per invånare och högre följsamhet till rekommendationer utan att volymen läkemedel avvek från övriga landsting.Då detta är en epidemiologisk studie kan samvariationer beskrivas. Däremot kan studien inte visa om samvariationerna också är uttryck för orsakssamband, eller i vilken riktning ett eventuellt orsakssamband skulle gå. Inte heller kan studien kontrollera för okända faktorer som kan tänkas påverka båda de variabler som samvarierar. Inventeringen och analysen av existerande indikatorer på effektiv och jämlik läkemedelsanvändning visar på en mängd metodproblem som försvårar studier av samband mellan styrformer och utfall. Det är därför angeläget att arbetet med att utveckla valida effektivitetsindikatorer fortsätter.
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  • Result 1-10 of 24
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other academic/artistic (6)
Author/Editor
Elofsson, Mikael (14)
Andersson, C. David (10)
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