广泛发现化学多样化的宏环胺
Patrick J Salveson1,2, Adam P Moyer1,2, Meerit Y Said1,2
1Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|April 25, 2024
概括
研究人员开发了一种计算方法来设计和合成新的小宏循环,为药物发现和基于结构的设计开辟了新的途径.
科学领域:
- 医学化学
- 计算化学
- 结构生物学
背景情况:
- 小型宏观循环是强大的自然产品,但缺乏系统的生成方法.
- 目前的局限性阻碍了药物开发的多样化宏环化学空间的探索.
研究的目的:
- 开发一种用于系统设计新型有序宏循环的计算方法.
- 通过计算设计的宏循环进行化学合成和结构验证.
- 证明设计的宏循环作为选择性抑制剂的治疗潜力.
主要方法:
- 使用计算方法识别各种氨基酸化学中的有序宏循环.
- 从超过42,000个单体组合中预测了1490万个独特的宏循环结构.
- 合成了18个预测的宏循环,并使用X射线和NMR光谱证实了它们的结构.
主要成果:
- 在18个合成的宏循环中,有15个与它们的计算设计模型非常相匹配.
- 证明了高结构忠实度的计算设计宏循环合成的可行性.
- 使用设计的宏循环开发了针对三种治疗相关蛋白质的选择性抑制剂.
结论:
- 开发的计算方法可以系统地生成多样化,类似于药物的宏循环.
- 这种方法显著扩大了基于宏观循环的药物设计的可访问化学空间.
- 预计这些发现将增强基于结构的药物设计并加速治疗开发.
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