A molecular modeling study of the interaction of 2 '-fuoro-substituted analogues of dUMP/FdUMP with thymidylate synthase

作者：Jarmula Adam^*; Dowiercial Anna; Rode Wojciech

来源：Bioorganic & Medicinal Chemistry Letters, 2008, 18(8): 2701-2708.

DOI：10.1016/j.bmcl.2008.03.016

• 2 '-fluoro-substituted dUMP/FdUMP analogues
• substrate-based inhibitors of thymidylate synthase
• thymidylate synthase
• molecular dynamics simulations
• MM-GBSA approach

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 20,5-diF-ara-UMP.

• 出版日期2008-4-15