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小分子准AR-V7部分失序蛋白质的结构动力学,使用深层合奏对接

Pantelis Karatzas¹, Z Faidon Brotzakis^2,3, Haralambos Sarimveis¹

¹School of Chemical Engineering, National Technical University of Athens, 9 Heroon Polytechniou Street, Athens 15780, Greece.

Journal of chemical theory and computation

|April 15, 2025

概括

这项研究引入了一个深层集体对接管道,以有效地选候选药物,以检测AR-V7等部分失序蛋白质,这对前列腺癌至关重要. 该方法识别了关键的结合部位,并加速了对调制剂的发现,如ChEMBL2003,影响蛋白质动态.

科学领域:

计算生物学计算生物学
药物发现药物发现药物发现
结构生物学结构生物学

背景情况:

部分失序的蛋白质对传统的药物发现具有重大挑战,因为它们的动态性质和众多的短暂结合点.
这种AR-V7拼接变体与前列腺癌的进展有关,使其成为关键的治疗点.

研究的目的:

开发和验证一个深层组合对接管道,以加速对部分失序蛋白进行药物查.
确定AR-V7蛋白的功能结合点,并发现调节其活性的小分子结合剂.

主要方法:

使用深层组合对接管道来分析AR-V7.7的构造组合.
使用尺寸缩小技术来识别功能相关的结合部位.
基于物理学的分子对接结合了对小分子结合剂进行选的机器学习模型.
原子学分子动力学模拟评估了已识别的结合剂对AR-V7动力学的影响.

主要成果:

管道确定了AR-V7在易于分相的区域上的功能结合点,将结合点的维度减少了90%.
与纯粹的对接相比,多绑定站点的成功率增加了17倍.
一种选定的化合物ChEMBL22003被发现可以降低AR-V7的 conformational entropy,并调节其易于分相的区域.

结论:

开发的深层组合对接管道有效地加速了对部分无序蛋白质的结合物的发现.
ChEMBL22003显示出作为AR-V7相分离调节器的潜力,为前列腺癌提供了一种新的治疗策略.

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