对胺二酸盐依赖酶的活性位点进行共价对接
Artem V Artiukhov1,2, Vasily A Aleshin1,2
1Department of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia.
Molecules (Basel, Switzerland)
|November 27, 2025
概括
这项研究通过模拟胺二酸盐 (ThDP) 依赖酶中的共价相互作用来增强分子对接. 改进的算法可以预测新药发现的蛋白质-连接体结合.
科学领域:
- 生物化学 生化学
- 计算化学的计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 在生物医学科学中,分子对接对于识别新型低分子调节剂至关重要.
- 目前的对接方法很难模拟连接体和酶共因子之间的共价相互作用.
- 依赖胺二酸盐 (ThDP) 的酶是改善共价相互作用建模的关键领域.
研究的目的:
- 增强分子对接算法,用于模拟共价相互作用.
- 为了特别改进涉及胺二酸盐 (ThDP) 和其依赖酶的相互作用的建模.
- 在ThDP-依赖的催化中,为蛋白质-配体复合体的形成提供预测工具.
主要方法:
- 使用了含有ThDP附加物与酶基质或抑制剂的蛋白质模板.
- 作为 (R) -或 (S) -基衍生物的准备的连接物模型.
- 使用Gnina框架与AD4或Vinardo进行对接模拟.
主要成果:
- 格尼娜框架支持与实验抑制潜力相一致的连接体构造.
- 观察到对化与非化的基质类似物在酸盐和分支链二氧酸脱酶中的差异性结合偏好.
- 在2-oxoglutarate dehydrogenase中发现了对化与非化的配体的反向或缺失的结合偏好.
结论:
- 对含有ThDP的酶的2氧酸类似物进行共价对接,为蛋白质 - 配体复合体的形成提供了预测能力.
- 这种增强的建模特别有用,当抑制剂在酶反应中模仿过渡状态时.
- 改进的方法支持开发针对ThDP依赖酶的新型治疗剂.
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