制药核心:自动生成基于蛋白质/连接体复合体的3D结构制药模型
Simona De Vita1, Ester Colarusso1, Maria Giovanna Chini2
1Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
Journal of chemical information and modeling
|May 10, 2024
概括
PharmaCore是一个自动化工作流程,用于生成基于3D结构的药模型. 这种药物发现工具使用蛋白质-连接体结构来预测结合模式并识别潜在的药物标或重新定位候选者.
科学领域:
- 计算化学是一种计算化学.
- 结构生物学是结构生物学.
- 药物发现 药物发现
背景情况:
- 药模拟对于理解药物标相互作用至关重要.
- 自动化工作流可以加速药物发现过程.
- 识别新药候选药物和重新定位现有药物需要高效的建模工具.
研究的目的:
- 介绍PharmaCore,一种全新的,完全自动化的工作流程,用于生成基于3D结构的药模型.
- 通过已知的目标和实验测试来验证PharmaCore工作流.
- 证明PharmaCore在药物发现和重新定位方面的实用性,包括目标外预测.
主要方法:
- 药芯利用共结晶的配体-蛋白质结构来产生药型假设.
- 一个Python库自动收集和对准基于UniProt ID的蛋白质-连接体复合体.
- 药模型是直接在蛋白质结构上使用专门的软件 (例如,Phase) 生成的.
主要成果:
- PharmaCore成功生成了可溶性环氧化酶 (sEH) 的药,与已公布的数据一致.
- 工作流确定了一个已知的ATAD2原蛋白结合剂 (AM879) 与表观遗传蛋白质面板之间的潜在非目标.
- 用AlphaScreen测试实验验证了计算预测,证实了工作流的适用性.
结论:
- PharmaCore为基于3D结构的药模型生成提供了强大的和自动化的解决方案.
- 该工作流适用于各种目标,包括tankyrase 2和SARS-CoV-2 Mpro.
- 通过PharmaCore,我们展示了加速药物发现和药物重新定位工作的巨大潜力.
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