NOVEL ANTI-CANCER DRUG DESIGN TARGETING AICAR TRANSFORMYLASE

针对 AICAR 转化酶的新型抗癌药物设计

• 批准号: 7955231
• 负责人: IAN A WILSON
• 金额: $ 3.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955231
• 关键词: Active Sites; Antineoplastic Agents; Biomedical Computing; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease; Drug Design; Enzymes; Folate; Folic Acid Antagonists; Funding; Generations; Grant; Hand; Hydroxymethyltransferases; Inflammatory; Institution; Kinetics; Normal Cell; Pathway interactions; Phosphoribosylglycinamide formyltransferase; Purines; Reaction; Research; Research Personnel; Resources; Rheumatoid Arthritis; Ribonucleotides; Source; Structure; United States National Institutes of Health; base; cancer cell; cluster computing; comparative; design; flexibility; imidazole carboxamide; inhibitor/antagonist; novel; pharmacophore; phosphoribosylaminoimidazolecarboxamide formyltransferase; purine; scaffold; Active Sites; Antineoplastic Agents; Biomedical Computing; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease; Drug Design; Enzymes; Folate; Folic Acid Antagonists; Funding; Generations; Grant; Hand; Hydroxymethyltransferases; Inflammatory; Institution; Kinetics; Normal Cell; Pathway interactions; Phosphoribosylglycinamide formyltransferase; Purines; Reaction; Research; Research Personnel; Resources; Rheumatoid Arthritis; Ribonucleotides; Source; Structure; United States National Institutes of Health; base; cancer cell; cluster computing; comparative; design; flexibility; imidazole carboxamide; inhibitor/antagonist; novel; pharmacophore; phosphoribosylaminoimidazolecarboxamide formyltransferase; purine; scaffold

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 癌细胞比正常细胞更严重地依赖于从头嘌呤生物合成途径，这有利于打捞 路径是他们的主要嘌呤来源。潜在抗癌药物的从头途径中的主要酶促靶标（S） 是两个叶酸依赖性转化基酶，糖酰胺核糖核苷酸转化基酶（GAR TFASE）和氨基 - 咪唑 羧酰胺核糖核苷酸转化基酶（AICAR TFASE）。十年前，GAR TFASE结构解决了。 但是，该酶在其活性位点具有许多灵活的环，这使基于结构的药物的问题更加复杂 设计和阐明其反应机制。最近的氟叶酸复合物结构显示了这种复合物 似乎最密切地代表了活跃状态结构。一项全面的比较自动库克研究验证了这一点 我们在基于结构的药物设计上持续努力的新结构模板。我们最近确定的AICAR TFase结构提出了一个新的目标。在某些方面，它将是一个更好的目标，因为它的动力学是独立于pH的，并且 它具有一个相对僵化的活性站点。 AICAR TFASE抑制剂也有可能用于治疗炎症性疾病， 例如类风湿关节炎。另一方面，非常需要发现替代的结构支架来设计 新一代的特定抑制剂，不仅是传统的抗污物，我们已经使用了自动库克来实际上筛选 通过利用NCRR/NBCR和SCRIPPS赞助的计算簇设置的药效团代理NCI多样性。