THEORETICAL STUDY OF ANTIFOLATES AS INHIBITORS OF THYMIDYLATE SYNTHASE

胸苷酸合酶（TS）催化dUMP和 5，10-CH 2-H4叶酸转化为dTMP。 它是dTMP的唯一已知路径 合成. dTMP的合成被认为是一种速率限制 DNA复制的步骤。 该酶的抑制剂可用于 阻断dTMP的合成，并可用于 癌的 我们进行了自由能微扰（FEP）计算， 具有不同的取代组合的所选分子 抑制剂的 计算结果与实验值吻合较好 用于选择缺乏谷氨酸残基的抑制剂。 大多数这些 化合物具有相同的 N-（（3，4-二氢-2-甲基-6-喹唑啉基）甲基）-N-丙-2-炔苯胺 结构 苯胺被简单的亲脂性取代， 在不同的位置取代。 一套画报 自由能变化的表示（PROFEC）计算也是 执行。 我们发现R5和R6上的氟取代 位置增强约束力。 最令人鼓舞的结果是， 化合物显示约6千卡/摩尔的结合增强。 它建议 R5或R6取代可能是设计的新方向， TS抑制剂。 计算机图形实验室是至关重要的， 设计抑制剂并查看PROFEC结果，特别是 3D能力。

Thymidylate Synthase (TS) catalyzes the conversion of dUMP and 5,10-CH2-H4folate into dTMP. It is the only known path for dTMP synthesis. dTMP synthesis is believed to be one of the rate limiting steps in DNA replication. The inhibitor of this enzyme can be used to block dTMP synthesis and can be of possible chemotherapeutic use for cancers. We performed Free Energy Perturbation (FEP) calculations on selected molecules with different combinations of substitutions of inhibitors. The calculation results agree with experimental values for selected inhibitors that lack glutamate residues. Most of these compounds have the same N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline structure. The aniline was substituted with simple lipophilic substituents at different positions. A set of Pictorial Representation of Free Energy Change (PROFEC) calculations was also performed. We found that fluorine-substitution at the R5 and R6 positions enhances binding. The most encouraging result is that one compound shows about 6 Kcal/mole binding enhancement. It suggested that R5 or R6 substitution could be a new direction for the design of TS inhibitors. The Computer Graphics Laboratory is crucial in designing the inhibitors and viewing the PROFEC results, especially the 3D ability.