A molecular modeling study of the interaction of 2′-fluoro-substituted analogues of dUMP/FdUMP with thymidylate synthase
- 作者：Adam Jarmuł ; a ; Anna Dowierciał ; Wojciech Rode
- 关键词：2′ ; -Fluoro-substituted dUMP/FdUMP analogues ; Substrate-based inhibitors of thymidylate synthase ; Thymidylate synthase ; Molecular dynamics simulations ; MM-GBSA approach
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：15 April 2008
- 卷：18
- 期：8
- 页码：2701-2708
- 文件大小：831 K
摘要
Molecular dynamics simulations and free energy calculations are presented, exploring previously described experimentally studied interactions of a series of 2′-fluoro-substituted dUMP/FdUMP analogues with thymidylate synthase (TS). The results show the inhibitory behaviors of 2′-F-ara-UMP, 2′,2″-diF-dUMP and 2′,5-diF-ara-UMP to be dependent upon the binding positions and orientations adopted by the molecules of these compounds in the active site of TS. The binding mode of 2′,5-diF-ara-UMP suggests a novel role of the active site residue Trp 80, stabilizing through hydrophobic stacking the binding position of the pyrimidine ring in 2′,5-diF-ara-UMP.