Synthesis, kinetics, and molecular docking of novel 9-(2-hydroxypropyl)purine nucleoside analogs as ligands of herpesviral thymidine kinases (CROSBI ID 95121)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Pospisil, Pavel ; D. Pilger, Beatrice ; Marveggio, Stefania ; Schelling, Pierre ; Wurth, Christine ; Scapozza, Leonardo ; Folkers, Gerd ; Pongračić, Mario ; Mintas, Mladen ; Raić-Malić, Silvana
engleski
Synthesis, kinetics, and molecular docking of novel 9-(2-hydroxypropyl)purine nucleoside analogs as ligands of herpesviral thymidine kinases
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-(2-hydroxypropyl)-substituted adenine, chloropurine, hypoxanthine, guanine, 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 range, comparable to binding affinities of existing prodrugs. Findings from the docking procedrure indicate multiple binding models for all of the compounds and are in accordance with the results of phosphorylation and binding-affinity studies. Furtermore, the studies reveal that hypoxanthine derivatives represent a new class of TK substrates and thiopurine derivatives a new class of TK inhibitors.
purine nucleoside analog synthesis ; herpesviral thymidine kinase ligand
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Podaci o izdanju
85 (10)
2002.
3237-3250
objavljeno
0018-019X
1522-2675
10.1002/1522-2675(200210)85:10<3237::AID-HLCA3237>3.0.CO;2-3