Jarmuła Adam, Dowierciał Anna, Rode Wojciech
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warszawa, Poland.
Bioorg Med Chem Lett. 2008 Apr 15;18(8):2701-8. doi: 10.1016/j.bmcl.2008.03.016. Epub 2008 Mar 10.
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.
本文展示了分子动力学模拟和自由能计算，探索了一系列2'-氟取代的dUMP/FdUMP类似物与胸苷酸合成酶（TS）之间先前已通过实验研究的相互作用。结果表明，2'-F-ara-UMP、2',2''-二氟-dUMP和2',5-二氟-ara-UMP的抑制行为取决于这些化合物分子在TS活性位点所采用的结合位置和取向。2',5-二氟-ara-UMP的结合模式表明活性位点残基色氨酸80具有新作用，即通过疏水堆积稳定2',5-二氟-ara-UMP中嘧啶环的结合位置。
