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.
Jarmuła
Adam
A
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warszawa, Poland. a.jarmula@nencki.gov.pl
Dowierciał
Anna
A
Rode
Wojciech
W
D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000737:chemistry* / Q000378:metabolism*
D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase