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新型USP5抑制剂的基于结构的虚拟查,针对指泛基素结合域

Tianhao Wang¹, Jianbo Tong², Xing Zhang¹

¹Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.

Computers in biology and medicine

|April 11, 2024

概括

研究人员发现了一种有前途的化合物,针对USP5,这是细胞蛋白平衡中的关键酶,与癌症等疾病有关. 这一发现为开发新的USP5抑制剂以对抗各种健康状况铺平了道路.

科学领域:

生物化学生物化学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

细胞蛋白质平衡对于生理功能至关重要.
USP5是一种双化酶 (DUB),调节蛋白质降解,并与癌症和神经退行性疾病等疾病有关.
准USP5为各种病理提供了治疗策略.

研究的目的:

为了确定针对USP5.5.的指泛胺结合域 (ZnF-UBD) 的新型抑制剂.
为了评估候选化合物的结合亲和力和稳定性.
为开发新的USP5向治疗提供洞察力.

主要方法:

多级虚拟查 (VS) 以确定潜在的抑制剂.
分子动力学 (MD) 模拟以评估结合稳定性和相互作用.
具有约束力的自由能量计算和雨采样 (US) 模拟以量化约束亲和力和形状变化.

主要成果:

一个有前途的候选化合物,0456-0049,被确定是针对USP5的ZnF-UBD.
MD模拟证实了该化合物的稳定结合,突出了关键的相互作用残留物 (ARG221,TRP209,GLY220,ASN207,TYR261,TYR259,MET266).
与已知的抑制剂相比,结合自由能量和美国模拟表明了优越的亲和力,并揭示了联结体解离过程中USP5构造变化.

结论:

鉴定的化合物对USP5.5具有强烈的结合亲和力和稳定性.
这些发现为设计新型USP5抑制剂提供了坚实的基础.
这项研究有助于开发针对USP5相关疾病的潜在治疗方法.

关键词:

有约束力的免费能源计算.分子动力学模拟模型使用USP5抑制剂.雨抽样是统一的抽样方式.虚拟选是一个虚拟的选.

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