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dc.contributor.advisorSylte, Ingebrigt
dc.contributor.authorLindin, Inger
dc.date.accessioned2015-01-07T12:58:08Z
dc.date.available2015-01-07T12:58:08Z
dc.date.issued2014-09-26
dc.description.abstractProtein kinases have become central in the efforts to understand the nature of various diseases, and a lot is invested into creating effective therapeutic strategies and finding effective and selective protein kinase inhibitors. In order to succeed it is also important to focus on the structure of the kinases, their exact biological role, and how they interact and cooperate in the signaling. The exact structure of MAPKAPK5 is still unknown, and selective inhibitors are yet to be identified. Even though some of its biological roles are starting to emerge more work is required, including searching for selective inhibitors, analyzing its structure and interactions with its interaction partners. In order to analyze the structure of MAPKAPK5, homology models were generated and their ability to discriminate between binders and non-binders were analyzed. Based on the results, one model was found satisfactory and may be used as a working tool for further experimental studies and possibly structure aided drug design. Further, interactions between MAPKAPK5 and its interaction partners were analyzed using molecular dynamic simulations. These studies showed that the previously created models were stable during simulations, and thereby robust and suitable for structural predictions. Simulation with MAPKAPK5 alone showed a stable kinase which maintained an active conformation. The simulations with an inhibitor indicated that the inhibitor binds to a MAPKAPK5 conformation consistent with an active protein kinase and thereby functions as an inhibitor by occupying the ATP binding site. The simulation with MAPKAPK5 in complex with the protein kinase p38 revealed that electrostatic interactions are important both for recognition and binding of p38, and that p38 bind to several areas in addition to the dedicated p38 binding site. This might be important when designing inhibitors which bind to other areas of MAPKAPK5 than the ATP binding pocket. Lastly, commercially available databases were searched for possible new MAPKAPK5 inhibitors. After computational and experimental testing several promising compounds were identified. These compounds might be a good starting point for synthesizing structurally modified analogues with improved potency and specificity and may contribute to further unraveling the functions of MAPKAPK5.en
dc.description.doctoraltypeph.d.en
dc.description.popularabstractProtein kinaser er en type enzymer i kroppen din som i de siste årene har blitt viktige for å forstå ulike sykdommer. Det forskes på å utvikle effektive terapeutiske strategier og finne effektive og selektive protein kinase hemmere. For å lykkes er det viktig å fokusere på den molekylære strukturen av kinaser, deres eksakte biologiske rolle, og hvordan de samhandler og samarbeider i cellene. Den nøyaktige strukturen til protein kinasen MAPKAPK5 er fortsatt ukjent, og selektive inhibitorer er ennå ikke er identifisert. Selv om noen av dens biologiske roller delvis er avklart, er det viktig å forske videre på dette. Blant annet er det viktig å finne selektive hemmere av dette enzymet, samt analysere dets struktur og rolle i cellen. For å analysere strukturen av MAPKAPK5 og deres evne til å skille stoffer som binder til enzymet fra stoffer som ikke binder enzymet ble molekylmodeller generert. Modellen som egent seg best ble brukt som arbeidsredskap for videre eksperimentelle studier. Videre ble interaksjoner mellom MAPKAPK5 og forskjellige stoffer analysert ved hjelp av molekylære dynamiske simuleringer. Til slutt ble kommersielt tilgjengelige databaser brukt til å søke etter nye MAPKAPK5 hemmere. Ved hjelp av eksperimentell testing ble flere lovende forbindelsene identifisert. Disse forbindelsene kan være gode utgangspunkt for å designe nye molekyler med forbedret virkning og spesifisitet mot MAPKAPK5.en
dc.description.sponsorshipUniversitetet i Tromsø (BioStruct)en
dc.descriptionPaper III of the thesis is not available in Munin:<br> III: Inger Lindin, Aina Westrheim Ravna, Sergiy Kostenko, Ingebrigt Sylte and Ugo Moens: “Discovery of Mitogen-activated protein kinase-activating kinase 5 inhibitors using virtual ligand screening”. (Manuscript)en
dc.identifier.urihttps://hdl.handle.net/10037/6998
dc.identifier.urnURN:NBN:no-uit_munin_6589
dc.language.isoengen
dc.publisherUiT The Arctic University of Norwayen
dc.publisherUiT Norges arktiske universiteten
dc.rights.accessRightsopenAccess
dc.subject.courseIDDOKTOR-003en
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Farmakologi: 728en
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Pharmacology: 728en
dc.titleMitogen-activated protein kinase-activated protein kinase 5 - Structure, function and inhibitionen
dc.typeDoctoral thesisen
dc.typeDoktorgradsavhandlingen


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