Die Hemmung der CyclinA-aktivierten cyclinabhängige Kinase2

Alleine der Vergleich der in-silico Daten der Verbindungsklasse A, der Anthranoide, im Vergleich zur CK-2, zeigt eine deutlich schlechtere Bindung zur Proteinkinase CDK2/cyclinA.

A-1 A-5 A-6 A-7 A-8 C-5 C-6 C-7 C-8 D-4 D-5 D-6

1,00E-09 1,00E-08

1,00E-07 1,00E-06 1,00E-05 1,00E-04

[6-10] Vergleich der Docking KD-Werte der CK-2 (rot) mit der der CDK2/cyclinA (blau)

Aufgrund der schlechten in-silico Voraussagen, wurden keine näheren Strukturauswertungen und darauf folgend auch keine in-vitro Enzymtests durchgeführt. Die Bindung des CyclinA an das CDK-Protein bewirkt eine Aktivierung des Proteinkomplexes.

Infolge dessen kommt es zu einer Konformationsänderung und damit einer Öffnung der ATP-Bindungsstelle. Somit sind unsere untersuchten Liganden und potentiellen Inhibitoren einfach volumenmäßig zu klein für diese Bindungsstelle. Folglich ist, für eine mögliche Stabilisierung über hydrophobe Wechselwirkungen und Wasserstoffbrückenbindungen, einfach die Distanz zwischen Ligand und einen Großteil der Aminosäuren der Bindungstasche zu groß.

6.2. Zusammenfassung

In der vorliegenden Arbeit konnten wir in den meisten Fällen eine weitestgehend selektive Hemmung der CK-2 zeigen und vielfach auch die Ursachen strukturell nachweisen.

Für die Zukunft ist eine Basis geschaffen, targetorientiert gezielte Inhibitormodifikationen vorzunehmen, um sowohl die Hemmung als auch die Selektivität entsprechend zu verändern und zukünftig noch verbessern zu können.

Ausblick

Die Aufklärung der verschiedenen Eingriffsmöglichkeiten in spezielle zelluläre Signalwege spielt nicht nur für neue therapeutische Pharmazeutika eine wichtige Rolle, sondern leistet auch in hohem Maße einen Beitrag über die Aufklärung toxikologisch relevanter Wirkungsmechanismen auf der Proteinebene. Die genaue Kenntnis über die Angriffspunkte eines toxikologischen Agens im Signaltransduktionsweg ermöglicht langfristig gesehen den gezielten Eingriff über Hemmung oder Aktivierung bestimmter Teilbereiche.

In Zukunft sollen auf diesem Gebiet, weitere Strukturmodifizierungen aus den vier Teilbereichen der Anthranoide untersucht werden, um noch systematischere Aussagen zu Struktur-Funktions-Beziehungen treffen zu können. Auch sollen die Bindungstaschen der CK1 und der GSK-3β, ähnlich wie in dieser Arbeit für die CK2 genauer untersucht werden und über Alignement-Analysen der Kinasen untereinander auch kleinere Abweichungen in der Lage der Aminosäuren bestimmt werden. Dies könnte einen weiteren Beitrag zur Ursachenforschung der Selektivität bestimmter Verbindungen, trotz hoher Konservierung der ATP-Bindungstaschen innerhalb der Kinasenfamilie, leisten.

Ein weiterer interessanter Aspekt liegt in der direkten Hemmung der GSK-3β, einem Schlüsseltarget und Effektor auch in Insulinsignalwegen. Biologische Testungen und weiterführende Untersuchungen auch in diese Richtung werden durchgeführt.

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Im Dokument Natürliche und chemisch modifizierte Polyphenole als Inhibitoren von Signalproteinen des Wnt/ß-catenin-Signaltransduktionsweges (Seite 89-101)