脂肪酸结合蛋白质结构的高分辨率数据集. 三,第三部分. 错误带的意外高发生率
Andreas Ehler1, Christian Bartelmus1, Joerg Benz1
1Therapeutic Modalities, Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
Acta crystallographica. Section D, Structural biology
|August 1, 2025
概括
针对FABP目标的基于结构的药物设计 (SBDD) 在15%的结构中揭示了意想不到的配体组成. 这突出了SBDD活动中的潜在问题,即使在高分辨率下,由于副作用.
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:
- 脂肪酸结合蛋白 (FABPs) 与代谢疾病有关.
- FABP4是糖尿病和动脉样硬化的关键治疗标.
研究的目的:
- 通过基于结构的药物设计 (SBDD) 来研究FABP异型的结合体结合结构.
- 识别SBDD活动中的潜在问题.
主要方法:
- 产生了人类FABP3,FABP4和FABP5.5的216个联结结构.
- 使用高吞吐量和碎片选用于初始命中.
- 采用基于结构的药物设计 (SBDD) 使用高分辨率晶体学 (1.2 Å 以上).
主要成果:
- 大约15%的配体呈现出意想不到的化学成分.
- 确定了包括添加,消除,同质化,循环化和二元化在内的副作用.
- 突出了SBDD的潜在不准确性,因为这些化学变异.
结论:
- 即使在高分辨率的SBDD活动中,也可能会遇到意想不到的配体组合.
- 连接体的化学修饰可以通过各种副作用发生.
- 这些发现强调了药物设计中严格的化合物验证的重要性.
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