Molecular Modelling Untersuchungen an der humanen Proteinkinase CK2 (English shop)

Preview

Table of Contents, Datei (35 KB)
Extract, Datei (120 KB)

Protein kinase CK2 (formerly known as casein kinase 2) is a Ser/Thr kinase belonging to the superfamily of the so-called eukaryotic protein kinases. It appears to be involved in a number of pathological processes such as tumorigenesis and viral survival, making it an interesting target for drug development. In this work, the molecular interactions of ligands with CK2 were investigated using computer-aided theoretical methods. First, on the basis of crystal structures of CK2α from Zea mays, a stereochemically permitted activated catalytic domain of the human enzyme (mhCK2α) was modelled by means of homology alignment methods; this model was then used to investigate the binding behaviour of ATP and GTP in the active site by molecular dynamics. As a result, the preference of the enzyme for ATP over GTP could be adequately simulated. In addition, information was obtained on the stability of co-crystallised water molecules involved in cosubstrate binding. In particular, two water molecules (Wat-A and Wat-B) appear to be essential for the dual cosubstrate specificity of CK2. Subsequently, the complexes of mhCK2α with the inhibitors emodin and IQA were subjected to MD investigations. Docking studies with indeno[1,2-b]indoles – new potent inhibitors of human CK2 – yielded binding geometries which, like those of typical CK2 inhibitors, lay absolutely coplanar to the natural cosubstrates ATP and GTP in the purine base binding plane. Molecular interaction fields in the active site calculated with GRID agreed very well with the interaction geometries found. MD simulations revealed a particularly stable binding mode for the indenoindole 6b. Starting from the binding mode of ligand 6b, a protein-based design of new structural variations of the indenoindoles was carried out using GRID in order to extend their interaction spectrum in the active site. In a subsequent docking analysis, these structures were scored significantly better than the parent compound 6b. An MD simulation of a new structure, L6b_02, supported the presumed very good stability of the proposed interaction geometries. On the basis of the proposed indenoindoles, a virtual screening of the drug-like molecule set from the ZINC database was performed to conclude this work. Using various filters (FTREES, visual analysis), a preselection of 44 structures was obtained for the subsequent docking analysis. Finally, the docking results were verified with GRID fields, and eight of the 20 best-scored structures were subjected to experimental testing.