移动性对MMPs基于结构的药物设计的影响
Franklin J Moy1, Pranab K Chanda, James Chen
1Department of Biological Chemistry Wyeth Research, 87 Cambridge Park Dr., Massachusetts 02140, USA.
Journal of the American Chemical Society
|October 24, 2002
概括
药物设计往往忽略了蛋白质动力学. 对于矩阵金属蛋白酶 (MMPs),活性位点的移动性解释了为什么化合物1出乎意料地与MMP-1结合,具有高亲和力,挑战静态结构预测.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药用化学 医学化学
背景情况:
- 基于结构的药物设计通常忽略了溶剂效应和蛋白质动态,限制了结合亲和力预测.
- 矩阵金属蛋白酶 (MMP) 已知具有显著的活性位移性,使使用静态模型复杂化药物设计.
研究的目的:
- 为了研究蛋白质动态对抑制剂结合亲和力的影响.
- 为了解释一种特定的胺酸衍生物 (化合物1) 对MMP-1的观察到的低纳米分子结合,尽管基于静态结构的选择性预测.
主要方法:
- 核磁共振 (NMR) 谱学以确定MMP-1:化合物1复合物的三维结构.
- 在MMP活性部位内分析抑制剂动态.
主要成果:
- 核磁共振结构揭示了MMP-1活性部位内化合物1的复杂动态.
- 这些动态解释了化合物1与MMP-1的意想不到的高结合亲和力,这与基于静态结构碰撞的预测相反.
结论:
- 蛋白质动态在抑制剂结合亲和力中起着至关重要的作用,必须在药物设计中考虑.
- 静态结构模型不足以准确预测灵活抑制剂与MMP等动态蛋白标的结合.
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