结构导向设计的AMP模仿抑制高亲和度和特异性的果糖-1,6-双酸酶
Mark D Erion1, Qun Dang, M Rami Reddy
1Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA. erion@mbasis.com
Journal of the American Chemical Society
|November 29, 2007
概括
研究人员设计了新的AMP模仿剂,以抑制果糖1,6-双酸酶 (FBPase),这是生产葡萄糖的关键酶. 这些强有力的抑制剂向AMP结合部位,通过减少葡萄糖生成,为2型糖尿病提供潜在的治疗策略.
科学领域:
- 生物化学 生化学
- 酶动力学 酶动力学
- 药物发现 药物发现
背景情况:
- 氨酸单酸 (AMP) 结合部位对于碳水化合物和脂质代谢酶的全调节至关重要.
- 准这些酶为代谢疾病提供了潜在的治疗策略.
研究的目的:
- 设计一种强大的果糖1,6-双酸酶 (FBPase) 抑制剂,模仿AMP结合.
- 探索FBPase的AMP结合部位作为代谢疾病的药物标.
主要方法:
- 结构导向药物设计包括分子建模和自由能量扰动计算.
- 进行X射线晶体学和酶动力学测试,以验证抑制剂的结合和效力.
- 在初级大鼠肝细胞中进行抑制研究,以评估途径水平的影响.
主要成果:
- 开发了一种新型的胺酸 (16) 结合FBPase AMP部位,具有高度亲和力和特异性.
- 化合物16比AMP强11倍,对人类FBPase的IC50为90nM.
- 肝细胞中由化合物16抑制FBPase导致减少葡萄糖生成.
结论:
- FBPase的AMP结合部位是治疗干预的可行目标.
- 新型AMP模仿剂可以被设计成强大且特别抑制FBPase.
- 针对FBPase提供了一种潜在的策略,以减少2型糖尿病中过量的葡萄糖产量.
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