超稳定受约束的准确的de novo设计
Gaurav Bhardwaj1,2, Vikram Khipple Mulligan1,2, Christopher D Bahl1,2
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Nature
|September 15, 2016
概括
研究人员开发了计算方法来设计结构上受限的. 这些新的稳定模仿自然结构, 提供新一代基于的疗法.
科学领域:
- 生物化学
- 计算生物学
- 药物设计
背景情况:
- 具有共价交叉链的自然存在的具有精确的目标结合的进化形状.
- 限制性提供了小分子药物特性 (稳定性,透性) 和蛋白质治疗特异性的混合物.
研究的目的:
- 开发构造受限制的新设计的计算方法.
- 为任意的生物目标创建形状补充抑制剂.
主要方法:
- 开发用于新设计的计算算法.
- 18-47残留物,二硫化物交联的设计,包括异体和骨干循环变体.
- 使用X射线和NMR结构确定进行实验验证.
主要成果:
- 设计的具有特殊的耐热和化学变性稳定性.
- 经过实验确定的结构与计算模型密切匹配,验证了设计方法.
- 证明了具有高可信度的结构限制的能力.
结论:
- 开发的计算方法使受约束的准确 de novo 设计成为可能.
- 稳定的基架为一种新的基于的疗法提供了基础.
- 这项工作使类药物的设计能够为特定的治疗目标量身定制.
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