Synthesis, Kinetics, and Molecular Docking of Novel 9-(2-Hydroxypropyl)purine Nucleoside Analogs as Ligands of Herpesviral Thymidine Kinases
✍ Scribed by Pavel Pospisil; Beatrice D. Pilger; Stefania Marveggio; Pierre Schelling; Christine Wurth; Leonardo Scapozza; Gerd Folkers; Mario Pongracic; Mladen Mintas; Silvana Raic Malic
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- German
- Weight
- 179 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0018-019X
No coin nor oath required. For personal study only.
✦ Synopsis
Dedicated to Dieter Seebach on the occasion of his 65th birthday
In the context of broadening the knowledge on substrate specificity of Herpes simplex virus type 1 thymidine kinase (HSV-1 TK) and Varicella-Zoster virus thymidine kinase (VZV TK), new derivatives of 9-(2hydroxypropyl)-substituted adenine, chloropurine, hypoxanthine, guanine, thiopurine, and (methylsulfanyl)purine were synthesized and subjected to in vitro phosphorylation and binding affinity assays. The interactions between the compounds and the crystallographically determined active site residues of HSV-1 TK have been studied by molecular modeling with the Lamarckian genetic algorithm of docking program AutoDock 3.0. All compounds mentioned bind to both enzymes in the low mm to sub-mm range, comparable to binding affinities of existing prodrugs. Findings from the docking procedure indicate multiple binding modes for all of the compounds and are in accordance with the results of phosphorylation and binding-affinity studies. Furthermore, the studies reveal that hypoxanthine derivatives represent a new class of TK substrates and thiopurine derivatives a new class of TK inhibitors.
Helvetica Chimica Acta ± Vol. 85 (2002) 1 H-and 13 C-NMR Spectra. Assignment of 1 H-and 13 C-NMR spectra was performed on the basis of chemical shifts, signal intensities, magnitude and multiplicity of C,H spin-spin coupling constants, as well as connectivity in NOESY and COSY spectra. The 1 H-and 13 C-NMR data of 1 ± 8 are collected in Tables and, respectively.