De Winter H, Herdewijn P
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
J Med Chem. 1996 Nov 22;39(24):4727-37. doi: 10.1021/jm960278v.
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 5-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 5-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.
单纯疱疹病毒1型胸苷激酶（HSV-1 TK）是抗病毒核苷代谢激活过程中的关键酶。此类化合物对该酶具有高亲和力是实现高效磷酸化所必需的。在本研究中，一系列5-取代2'-脱氧尿苷底物的亲和力数据与该病毒酶的晶体结构相结合，用于研究影响这些化合物对该酶亲和力的结构因素。计算结果表明，胸苷以及5-取代2'-尿苷类似物的结合能和构象相似。结合能的主要部分源于涉及糖基和碱基部分的相互作用。对该酶亲和力的微小差异可通过5-取代基的疏水性或其与活性位点口袋的能量互补性来解释。在设计HSV-1 TK的高亲和力核苷底物时，应注意保持碱基部分的几何形状和糖羟基官能团。核苷碱基5-位的取代基应为亲脂性，并具有明确的几何特性。本研究首次对5-取代2'-脱氧尿苷的HSV-1 TK亲和力进行了定量解释，5-取代2'-脱氧尿苷是历史上第一类选择性抗病毒药物。这些结果可用于设计新型且更有效的化合物。
