订序宏循环的综合计算设计
Parisa Hosseinzadeh1, Gaurav Bhardwaj1, Vikram Khipple Mulligan1
1Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|December 16, 2017
概括
研究人员开发了一种计算方法来设计新的混合性大循环. 这种方法极大地扩大了药物发现和治疗开发的结构多样性.
科学领域:
- 医学化学
- 计算化学
- 结构生物学
背景情况:
- 混合性大循环,如环素,是强大的治疗药物.
- 现有的方法缺乏系统的方法来探索这些化合物的结构多样性.
- 自然蛋白质是设计新宏循环的糟糕模板.
研究的目的:
- 开发一种计算策略来列举混合性大循环的稳定结构.
- 设计用于药物发现的新宏循环支架.
- 用实验结构验证计算预测.
主要方法:
- 几乎完全的宏环的骨干采样.
- 序列设计和能源景观计算.
- 核磁共振 (NMR) 结构的确定.
主要成果:
- 确定了超过200个设计的宏循环,预计采用单一的稳定结构.
- 设计的宏循环的实验结构与计算模型密切相匹配.
- 显示可用的宏循环支架的显著扩张.
结论:
- 开发的计算方法提供了对短周期结构空间的全面覆盖.
- 这项工作大大增加了合理药物设计和图书馆选择的起点.
- 能够系统地探索和设计新的治疗性大循环.
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