THEORETICAL STUDY OF ANTIFOLATES AS INHIBITORS OF THYMIDYLATE SYNTHASE

抗叶酸药作为胸苷酸合酶抑制剂的理论研究

• 批准号: 6347966
• 负责人: TAI-SUNG LEE
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347966
• 关键词: AIDS; biological products; biomedical resource; computers; enzymes; immunology; infection; inflammation; lymphatic system; nucleic acids; technology /technique; virus

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.

胸苷合成酶(TS)催化DUMP和 5，10-CH2-H4叶酸加入DTMP。这是唯一已知的DTMP路径 综合。DTMP的合成被认为是速度限制之一 DNA复制的步骤。这种酶的抑制剂可以用来 阻断DTMP的合成并可能用于化疗 癌症。我们进行了自由能微扰(FEP)计算 具有不同取代基组合的选定分子 抑制剂。计算结果与实验值吻合较好。 用于缺乏谷氨酸残留物的选定抑制剂。其中大多数都是 化合物具有相同的 N-((3，4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline 结构。用简单的亲脂性取代了苯胺。 不同位置的取代基。一套画报 自由能变化(PROFEC)计算的表示也是 已执行。我们发现R5和R6上的氟取代 位置增强了约束性。最鼓舞人心的结果是 化合物的结合能力提高了约6Kcal/摩尔。它建议 R5或R6的替代可能是设计的一个新方向 TS抑制剂。计算机图形学实验室在 设计抑制剂和查看PROFEC结果，尤其是 3D能力。