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Synthesis, Kinetics, and Molecular Docking of Novel 9‐(2‐Hydroxypropyl)purine Nucleoside Analogs as Ligands of Herpesviral Thymidine Kinases
Author(s) -
Pospisil Pavel,
Pilger Beatrice D.,
Marveggio Stefania,
Schelling Pierre,
Wurth Christine,
Scapozza Leonardo,
Folkers Gerd,
Pongracic Mario,
Mintas Mladen,
Malic Silvana Raic
Publication year - 2002
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(200210)85:10<3237::aid-hlca3237>3.0.co;2-3
Subject(s) - chemistry , thymidine kinase , docking (animal) , guanine , autodock , hypoxanthine , kinase , nucleoside , biochemistry , stereochemistry , prodrug , purine , enzyme , herpes simplex virus , nucleotide , virus , virology , biology , medicine , nursing , gene , in silico
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, 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 m M to sub‐m M 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.