In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses,Journal of Medicinal Chemistry

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In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-04-12 , DOI: 10.1021/acs.jmedchem.1c02155
Junzhuo Liao ₁ , Xueqing Nie ₁ , Ilona Christy Unarta ₂ , Spencer S Ericksen ₃ , Weiping Tang _{1,

2,

3}

Affiliation

Proteolysis targeting chimeras (PROTACs) are molecules that induce protein degradation via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. The rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC-induced ternary complex. This study demonstrates that native and non-native ternary complex poses can be distinguished based on the pose occupancy time in MD, where native poses exhibit longer occupancy times at both room and higher temperatures. Candidate poses are generated by MD sampling and pre-ranked by classic MM/GBSA. A specific heating scheme is then applied to accelerate ternary pose departure, with the pose occupancy time and fraction being measured. This scoring identifies the native pose in all systems tested. Its success is partially attributed to the dynamic nature of pose departure analyses, which accounts for entropic effects typically neglected in the faster static scoring methods, while entropy plays a greater role in protein–protein than in protein–ligand systems.

中文翻译：

PROTAC 介导的三元复杂姿势的计算机模拟和评分

蛋白水解靶向嵌合体 (PROTAC) 是通过在 E3 泛素连接酶和靶蛋白之间形成三元复合物来诱导蛋白质降解的分子。PROTAC 的合理设计需要准确了解 PROTAC 诱导的三元复合物的天然构型。这项研究表明，可以根据 MD 中的姿势占用时间来区分本地和非本地三元复杂姿势，其中本地姿势在室温和更高温度下都表现出更长的占用时间。候选姿势由 MD 采样生成，并由经典 MM/GBSA 预先排序。然后应用特定的加热方案来加速三元位姿偏离，并测量位姿占用时间和分数。该评分标识了所有测试系统中的自然姿势。

更新日期：2022-04-12

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