Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of 1,5-anhydrohexitol nucleosides is described. These nucleoside analogues were obtained by alkylation of the heterocyclic bases with the tosylate 10 or by alkylation of the bases with the alcohol 12 under Mitsunobu conditions. The compounds were evaluated for antiviral and cytostatic activity. Highly selective activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) was noted for 1,5-anhydro-2,3-dideoxy-2-(5-iodouracil-1-yl)-D-arabino-hexitol 4b at a concentration of 0.07 microgram/mL. This activity must be dependent on a specific phosphorylation by the virus-encoded thymidine kinase (TK), since compound 4b was inactive against TK-deficient mutants of HSV-1. The corresponding cytosine 4c and guanine 4e analogues showed activity against HSV-1, HSV-2, and other herpes viruses (i.e. cytomegalovirus, varicella-zoster virus) at concentrations well below the cytotoxicity threshold (2 and 20 micrograms/mL, respectively). At these concentrations, compounds 4c and 4e proved also inhibitory to the growth of human T-cells (i.e. MT-4, CEM, MOLT-4).
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PMID:Synthesis and antiherpes virus activity of 1,5-anhydrohexitol nucleosides. 839 14

In an earlier study, De Winter and Herdewijn (J. Med. Chem. 1996, 37, 4727-4737) studied the binding of various 5-substituted 2'-deoxyuridine substrates to thymidine kinase of herpes simplex virus type-1. They used a computational procedure that achieves good correlation with experimentally determined IC50 values. We applied an alternative procedure to the same deoxyuridine substrates, using only three readily calculated quantities-the binding energy, the molecular surface area, and a flexibility factor. Our simplified method achieves the same degree of correlation with the IC50 values as did the earlier procedure. We then applied this procedure to examine the binding of various 5-substituted pyrimidine 1,5-anhydrohexitol substrates to thymidine kinase.
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PMID:Molecular modeling of the binding of 5-substituted 2'-deoxyuridine substrates to thymidine kinase of herpes simplex virus type-1. 1511 23