Publikationsserver der Universitätsbibliothek Marburg
Titel:Proteindynamik - Flexibilität in Zielproteinen des strukturbasierten Wirkstoffdesigns
Autor:Terwesten, Felix
Weitere Beteiligte: Klebe, Gerhard (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2018/0049
DOI: https://doi.org/10.17192/z2018.0049
URN: urn:nbn:de:hebis:04-z2018-00497
DDC:540 Chemie
Titel (trans.):Proteindynamics - Flexibility in Targets of Structure-Based Drug Design
Publikationsdatum:2018-01-18
Lizenz:https://creativecommons.org/licenses/by-nc-nd/4.0/

Dokument

Schlagwörter:
cryptic binding sites, Shigella, Protein-Arginin-Methyltransferasen, Aldosereduktase, tRNA-Guanin Transglykosylase, structure-based drug design, TGT, homology modeling, PRMTs, transient binding pockets, computer-aided drug design, transiente Bindungstas, Aldo-Keto-Reduktasen

Zusammenfassung:
In der vorliegenden Arbeit wurden unterschiedliche Methoden des computergestützten strukturbasierten Wirkstoffdesigns in verschiedenen Projekten zur Anwendung gebracht. // Es wurden dabei fünf verschiedenen Zielproteine in drei Targetklassen untersucht. (1) Aus der Superfamilie der Aldo-Keto-Reduktasen wurden zwei Mitglieder der Familie 1 untersucht: Zum einen Aldosereduktase, die auf Grund ihrer Beteiligung an diabetischen Komplikationen im fortgeschrittenen Stadium dieser Erkrankung von Interesse ist, zum anderen das Mitglied AKR1B10 dieser Familie, dessen Überexpression mit verschiedenen Krebsarten assoziiert ist. (2) PRMT4 und PRMT6, die als epigenetische Zielproteine ein aktuelles und zukunftsträchtiges Themengebiet darstellen. (3) Ein bakterielles Target in dieser Arbeit stellte die tRNA-Guanin Transglykosylase (TGT) dar, die auf Grund ihrer initialen Funktion in der Aktivierungskaskade des pathogenen Phänotyps von Shigella flexneri ein interessantes Target für die Behandlung der durch Shigellen ausgelösten Bakterienruhr darstellt. //// Aldosereduktase // Die AR gehört zu der Superfamilie der Aldo-Keto-Reduktasen. Als NAD(P)(H)-abhängige Oxidoreduktase ist sie in erster Linie für die Umwandlung von Glukose zu Sorbitol im Polyolweg bekannt. Darüber hinaus leistet sie durch die Reduktion von giftigen Aldehyden und Carbonylen einen wichtigen Beitrag zur Entgiftung des Organismus. Die Aldosereduktase wurde in Kooperation mit der Arbeitsgruppe Diederich (Marburg) und GE Healthcare Bio-Sciences AB untersucht. Der Fokus dieses Projekts lag auf der Charakterisierung einer Ligandenserie und Untersuchung des Bindungsverhaltens dieser Liganden in Hinblick auf das Öffnungsverhalten der transienten Spezifitätstasche des Proteins. Der Beitrag dieser Dissertation war die Untersuchung der Proteindynamik im Bezug auf diese Tasche und die Analyse und Beschreibung eines möglichen Öffnungsmechanismus. Die Daten für diese Analysen wurden durch molekulardynamische Simulationen gewonnen. Ein weiterer Beitrag war die Durchführung von MM-GBSA-Berechnungen zur Evaluierung der Bindungspräferenz zweier ähnlicher Liganden in Bezug auf die Spezifitätstasche. // AKR1B10 // In diesem Kooperationsprodukt wurden vergleichende Simulationen eines Liganden (JF0064) durchgeführt, um (1) die röntgenkristallographisch beobachtete Protonierung des Liganden im Komplex mit dem Protein zu validieren und (2) strukturelle Einblicke in die Bindungskonformation des Liganden im Komplex mit dem Wildtyp-Protein zu bieten. Die molekulardynamischen Simulationen boten hier einen Einblick in die Struktur des Wildtyp:JF0064-Komplexes, dessen röntgenkristallographische Aufklärung nicht möglich war. // Protein-Arginin-Methyltransferasen // In diesem Kapitel wurden verschiedene Verfahren verwendet, um zwei Aufgabenstellungen umzusetzen. (1) In Kooperation mit der Arbeitsgruppe Bauer wurde ein Homologiemodell für die Gallus gallus PRMT4 erstellt. Bisher wurde in Vögeln, als einziger Klasse der Wirbeltiere, kein PRMT4-Homolog nachgewiesen. Hannah Berberich gelang erstmalig der Nachweis einer putativen Gallus gallus PRMT4 (ggPRMT4). Der Anteil dieser Dissertation war die Erstellung eines plausiblen in silico Modells der ggPRMT4. Dafür wurden verschiedene in silico Methoden miteinander kombiniert. Im Rahmen dieses Projekts wurde zur Erstellung des ggPRMT4-Modells eine Homologiemodellierung kombiniert mit einem Protein-Protein-Docking durchgeführt. Die Validierung und Untersuchung der Dynamik des modellierten Komplexes erfolgte durch ergänzende molekulardynamische Simulationen. (2) Im Rahmen eines Dockings von organischen Kleinmolekülen wurden die beiden Proteine PRMT4 und PRMT6 – ausgehend von bekannten Kristallstrukturen – als Targets adressiert. Diesen Dockingläufen schloss sich die visuelle Inspektion der durch Scoring-Funktionen vorselektierten Moleküle an. Anschließend wurden interessante Verbindungen kommerziell erworben und in Kooperation mit der Arbeitsgruppe Bauer von Antje Repenning in einem Assay getestet. Dabei konnten aktive Substanzen gefunden werden, die nun weiter untersucht werden und als Ausgangspunkte für rationales Wirkstoffdesign dienen können. // tRNA-Guanin Transglykosylase // Dieses Target wurde im Rahmen von zwei Studien untersucht. In (1) wurde zunächst die Dynamik einer bei röntgenkristallographischen Untersuchungen neu entdeckten Subtasche unter der beta1alpha1-Schleife untersucht. Dabei erfolgte die Untersuchung erst mit Hilfe molekulardynamischer Simulationen. Im zweiten Schritt wurde diese Tasche dann in einem Docking mit organischen Molekülen adressiert. In (2) wurde das Öffnungsereignis der transienten erweiterten Guanin/preQ1-Bindetasche durch molekulardynamische Simulationen analysiert.

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