Title
Understanding the binding of 5-substituted 2'-deoxyuridine substrates to thymidine kinase of herpes simplex virus type-1 Understanding the binding of 5-substituted 2'-deoxyuridine substrates to thymidine kinase of herpes simplex virus type-1
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
39(1996) :24 , p. 4727-4737
ISSN
0022-2623
ISI
A1996VU59500005
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
Thymidine kinase from HSV-1 (HSV-1 TK) is a key enzyme in the metabolic activation of antiviral nucleosides. High affinity of such compounds for the enzyme is required for efficient phosphorylation. In this study, affinity data from a series of 5-substituted 2'-deoxyuridine substrates in combination with the crystal structure of the viral enzyme were used to investigate the structural factors influencing the affinity of these compounds for the enzyme. Calculations showed that the binding energetics and conformations of thymidine and the g-substituted 2'-uridine analogues are similar. The major part of the binding energy arises from interactions involving sugar and base moieties. Small differences in affinity for the enzyme are explained by the hydrophobicity of the 6-substituent or by its energetic complementarity with the active site pocket. In designing high-affinity nucleoside substrates of HSV-1 TK, care should be taken to maintain the geometry of the base moiety and sugar hydroxyl functionalities. Substitutions at the 5-position of the nucleobase should be lipophilic and characterized by well-defined geometrical properties. The present study represents a first quantitative explanation for HSV-1 TK affinity of 5-substituted 2'-deoxyuridines which are historically the first group of selective antivirals. The results may be used to design new and more potent compounds.
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