STUDIES ON FOLIC ACID

二氢叶酸还原酶(Dhfr)是一种普遍存在的酶，也是靶标。 用于抗叶酸药物。抗叶酸具有持续重要性，而不是 不仅在肿瘤疾病中，而且在自身免疫方面也越来越有用 疾病、与艾滋病相关的机会性并发症(包括寄生虫 和细菌感染)和一般的此类感染。存在的问题 现有药物的广泛毒性和缺乏选择性 如甲氨蝶呤(MTX)和甲氧苄啶(TMP)提供了动力 进一步研究。定量构效关系的相关技术 活动关系)是这样一种方法来了解 调节配体(药物)与其靶标相互作用的作用力， 从而提出了基地中结构变化的最小数量 化合物，以获得一种具有独特选择性和效力的抑制剂。 DHFR是唯一可以通过QSAR进行分析的系统，因为不仅X射线 鸡肉中还原酶的晶体结构 肝脏、大肠埃希氏菌和干酪乳杆菌也有数百个密切相关 抗叶酸抑制剂已被合成。 利用本实验室开发的方法，从几种动物中提取DHFR 来源已得到广泛净化，可供调查 酶的性质、作用机制和与之相互作用 代谢抑制剂和药物，在合作研究中。 5-(取代)一系列化合物对鸡肝DHFR的抑制作用 对2，4-二氨基嘧啶类化合物进行了参数分析 与阻聚剂芳香族侧链上的取代基有关， 包括疏水性、摩尔折射率、哈米特常数等 指标变量以及极地和非极地相互作用。而QSAR 结果似乎与X射线结晶学大体一致 模型在2.8-A分辨率下，对特定结构细节的预测是 目前还不可能。

Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that is the target for the antifolate drugs. The antifolates are of continuing importance not only in neoplastic disease, but also of increasing utility in autoimmunine disorders, AIDS-related opportunistic complications (including parasitic and bacterial infections) and such infections in general. Problems of extensive toxicity and lack of selectivity of the currently available drugs such as methotrexate (MTX) and trimethoprim (TMP) provide the impetus for further study. The correlation techniques of QSAR (quantitative structural activity relationships) are such an approach to gain understanding of the forces that mediate the interaction of ligands (drugs) with their targets, thus suggesting the minimum number of structural variations in a base compound to achieve an inhibitor that is uniquely selective and potent. DHFR is a unique system to analyze via QSAR since not only are the X-ray crystallographic structures well defined for the reductases from chicken liver, E. coli and L. casei, but also hundreds of closely related antifolate inhibitors have been synthesized. Using methods developed in this laboratory, DHFR from several animal sources have been extensively purified and are available for investigation of enzymatic properties, mechanism of action, and interaction with metabolic inhibitors and drugs, in collaborative studies. The inhibition of chicken liver DHFR by a series of 5- (substituted benzyl)-2, 4-diaminopyrimidines was analyzed in terms of parameters relating to substituents on the aromatic side chains of the inhibitor, including hydrophobicity, molar refractivity, the Hammet constant, certain indicator variables and polar and non-polar interactions. While the QSAR results appear to be in general agreement with X-ray crystallographic models at 2.8-A resolution, prediction of specific structural details is not yet possible.