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

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.