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。 癌细胞比正常细胞更严重地依赖从头合成的嘌呤生物合成途径，而正常细胞更有利于挽救。 途径为其主要的嘌呤来源。潜在抗癌药物从头途径的主要酶靶点(S) 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 羧酰胺核糖核苷酸转移酶(AICAR Tfase)。GAR Tfase结构在十多年前就解决了； 然而，这种酶在其活性部位有许多灵活的环，这加剧了基于结构的药物的问题 设计并阐明了其反应机理。最近的氟叶酸络合物结构揭示了这个络合物 似乎最能代表活跃的国家结构。一项全面的AutoDock比较研究证实了这一点 为我们在基于结构的药物设计方面的持续努力提供新的结构模板。我们最近确定的AICAR Tfase结构呈现了一个新的靶点。在某些方面，它将是一个更好的靶点，因为它的动力学与pH无关，而且 它有一个相对刚性的活性部位。AICAR Tfase抑制剂在治疗炎症性疾病方面也有潜在的用途， 比如类风湿性关节炎。另一方面，人们非常希望找到替代的结构脚手架(S)来设计 新一代的特异性抑制剂，而不仅仅是传统的抗叶酸，我们已经使用AutoDock来虚拟筛选 药效团-利用NCRR/NBCR和Scripps赞助的计算集群设定的具有代表性的NCI多样性。

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.