NOVEL ANTI-CANCER DRUG DESIGN TARGETING AICAR TRANSFORMYLASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与正常细胞相比，癌细胞更严重地依赖于从头合成的嘌呤生物合成途径，而正常细胞倾向于将挽救途径作为其主要的嘌呤来源。在潜在的抗癌药物S的从头反应途径中，主要的酶靶点是两种叶酸依赖的转换酶，甘氨酰胺核糖核苷酸转换酶(GAR Tfase)和氨基咪唑甲酰胺核糖核苷酸转换酶(AICAR Tfase)。GAR Tfase的结构在十多年前就被解决了，然而，这种酶在其活性部位有许多灵活的环，这使得基于结构的药物设计和反应机理的阐明变得更加困难。最近的氟叶酸络合物结构表明，该络合物似乎最接近于活性状态结构。一项全面的AutoDock比较研究验证了这种新的结构模板，可用于我们在基于结构的药物设计方面的持续努力。我们最近确定的AICAR Tfase结构提供了一个新的目标。在某些方面，它将是一个更好的靶子，因为它的动力学与pH无关，而且它有一个相对刚性的活性中心。AICAR Tfase抑制剂也有可能用于治疗炎症性疾病，如类风湿性关节炎。另一方面，人们非常希望发现替代的结构支架(S)来设计新一代特异性抑制剂，而不仅仅是传统的抗叶酸。我们已经使用AutoDock通过利用NCRR/NBCR和Scripps赞助的计算集群来虚拟筛选具有药效团代表性的NCI多样性集。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer cells rely more heavily on the de novo purine biosynthetic pathway than normal cells, which favor the salvage pathway as their main purine source. The main enzymatic targets in the de novo pathway for potential anti-cancer drug(s) are two folate-dependent transformylases, glycinamide ribonucleotide transformylase (GAR Tfase) and amino-imidazole carboxamide ribonucleotide transformylase (AICAR Tfase). The GAR Tfase structure was solved over a decade ago; however, the enzyme has many flexible loops in its active site that has compounded the problem of structure-based drug design and elucidation of its reaction mechanism. A recent fluorofolate complex structure has revealed that this complex seems to most closely represent the active state structure. A comprehensive comparative AutoDock study validated this new structural template for our continuing efforts on structure-based drug design. Our more recently determined AICAR Tfase structure presents a new target. In some ways it will be a better target because its kinetics are pH-independent and it has a relatively rigid active site. AICAR Tfase inhibitors also have potential use in treatment of inflammatory diseases, such as rheumatoid arthritis. On the other hand, it is highly desirable to discover alternative structural scaffold(s) to design a new generation of specific inhibitors, not just the traditional antifolates, We already used AutoDock to virtually screen the pharmacophore-representative NCI Diversity Set by utilizing NCRR/NBCR and Scripps sponsored computing clusters.