IDENTIFICATION OF NEW ACETYL-COA CARBOXYLASE INHIBITORS

新型乙酰辅酶A羧化酶抑制剂的鉴定

• 批准号: 6831532
• 负责人: TEDD D ELICH
• 金额: $ 10万
• 依托单位: CROPSOLUTION, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831532
• 关键词: X ray crystallography; acetyl coA carboxylase; binding sites; biotin; chemical binding; communicable diseases; drug design /synthesis /production; drug discovery /isolation; enzyme inhibitors; fluoresceins; fluorescence polarization; gene expression; intermolecular interaction; molecular cloning; noninsulin dependent diabetes mellitus; obesity; protein purification; small molecule

DESCRIPTION (provided by applicant): Acetyl CoA carboxylase catalyzes the first step in fatty acid biosynthesis and is a key regulator of fat metabolism. Because of ACC's role in regulating fat storage and fat burning, pharmaceutical inhibitors of ACC have promise as treatments for obesity and type 2 diabetes - two urgent US health problems. Because ACC also plays a role in primary metabolism, ACC inhibitors additionally could prove useful as antimicrobial compounds. Currently there are no ACC inhibitors suitable as leads for drug development. The most potent ACC inhibitor known is the structurally complex, natural product soraphen. We propose to identify new small molecule inhibitors of ACC that target the soraphen binding site and that are suitable as leads for drug development. In phase I we will develop the necessary research tools: 1) isolated soraphen binding domains, derived from ACC, to be used as screening agents and in structural studies, 2) a microtiter plate-based assay to screen for new chemical inhibitors that target the soraphen binding site, and 3) structural information on the molecular interactions by which soraphen inhibits ACC. In phase II we will take an integrated approach incorporating the validated assay, in combination with computational chemistry methods based on the acquired structural information, in order to identify novel and synthetically tractable chemical leads that inhibit ACC. The long-term goal is to use these leads to develop and commercialize therapeutics for the treatment of obesity, type 2 diabetes, and microbial infections.

描述（申请人提供）：乙酰辅酶a羧化酶催化脂肪酸生物合成的第一步，是脂肪代谢的关键调节因子。由于ACC在调节脂肪储存和脂肪燃烧方面的作用，ACC的药物抑制剂有望治疗肥胖和2型糖尿病——这是美国两大紧迫的健康问题。由于ACC也在初级代谢中发挥作用，ACC抑制剂也可能被证明是有用的抗菌化合物。目前还没有合适的ACC抑制剂作为药物开发的先导物。已知最有效的ACC抑制剂是结构复杂的天然产物sorphen。我们建议鉴定新的靶向soraphen结合位点的ACC小分子抑制剂，这些抑制剂适合作为药物开发的先导。在第一阶段，我们将开发必要的研究工具：1)从ACC中分离出sorphen结合域，用作筛选剂和结构研究；2)基于微滴板的检测方法，筛选针对sorphen结合位点的新化学抑制剂；3)sorphen抑制ACC的分子相互作用的结构信息。在第二阶段，我们将采用一种综合的方法，结合基于获得的结构信息的计算化学方法，结合验证的分析，以确定抑制ACC的新型和合成可处理的化学先导物。长期目标是利用这些线索开发和商业化治疗肥胖、2型糖尿病和微生物感染的疗法。