NOVEL ANTI-CANCER DRUG DESIGN TARGETING AICAR TRANSFORMYLASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 癌细胞比正常细胞更依赖于从头嘌呤生物合成途径，这有利于挽救 途径作为其主要嘌呤来源。潜在抗癌药物从头途径中的主要酶靶点 是两种叶酸依赖性转化酶，甘氨酰胺核糖核苷酸转化酶（GAR Tfase）和氨基咪唑 羧酰胺核糖核苷酸转化酶（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，这使得基于结构的药物的问题更加复杂。 反应机理的设计和阐明。最近的一个氟叶酸复合物结构表明，这种复合物 似乎最能代表活跃的状态结构。一项全面的AutoDock比较研究证实了这一点 新的结构模板为我们继续努力的结构为基础的药物设计。我们最近确定的AICAR 转相酶结构提出了一个新的靶点。在某些方面，它将是更好的靶标，因为其动力学不依赖于pH， 它具有相对刚性的活性部位。AICAR Tfase抑制剂还具有治疗炎性疾病的潜在用途， 例如类风湿性关节炎。另一方面，高度期望发现替代的结构支架来设计 新一代的特异性抑制剂，而不仅仅是传统的抗叶酸剂，我们已经使用AutoDock来虚拟筛选 通过利用NCRR/NBCR和Scripps赞助的计算集群来构建代表药效团的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.