将D-Ala-D-Lac对万科米辛结合亲和力的损失划分为失去的H-键和排斥的单双贡献
Casey C McComas1, Brendan M Crowley, Dale L Boger
1Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|August 2, 2003
概括
在Ac2-l-Lys-d-Ala-d-Ala中用甲基替换一个胺基,显著改变了万科米辛的结合亲和力. 化合物5显示了1000倍的减少,主要是由于静电相互作用,而不是键损失.
科学领域:
- 药用化学 医学化学
- 分子相互作用 分子相互作用
- 药物发现 药物发现 药物发现
背景情况:
- 范科米辛是一种关键的抗生素,向细菌细胞壁合成.
- 了解菌素-配体相互作用是开发新抗生素的关键.
- 糖甘前体的结构性修改会影响胺素的结合.
研究的目的:
- 为了研究用甲基替换胺结合物的效果,对万科米辛的结合亲和力.
- 为了比较改性糖素前体 (化合物4和5) 与标准前体 (化合物3) 的结合亲和力.
- 阐明负责改变结合亲缘关系的特定分子相互作用.
主要方法:
- 合成改性糖素前体:化合物4 (甲基联结) 和化合物5 (联结).
- 化合物3,4和5与vancomycin的结合亲和力研究进行比较.
- 计算分析以确定键和静电相互作用的能量贡献.
主要成果:
- 与化合物3相比,化合物4对万科米辛的结合亲和力降低了10倍.
- 与化合物3相比,化合物5对万科米辛的结合亲和力降低了1000倍.
- 化合物5的降低亲和力主要归因于涉及氧的破坏稳定的单对/单对静电相互作用 (2.6 kcal/mol),而不是键的损失 (1.5 kcal/mol).
结论:
- 丁糖素前体中的胺结合对于高亲缘关系的胺结合至关重要.
- 由链引入的静电排斥显著减少了万科米辛的结合.
- 结构修改,特别是影响静电相互作用的结构修改,可以大大改变抗生素的疗效,为新药设计提供了洞察力.
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