Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies
Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies
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DOI：
10.1021/acs.jcim.0c00897
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发表时间：
2020-10-26
影响因子：
5.6
通讯作者：
Williams, Christopher, I
中科院分区：
文献类型：
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作者：
Drummond, Michael L.;Henry, Andrew;Williams, Christopher, I
在我们之前发表的基础上进行扩展[Drummond，M.；et al.J·化学。信息模特。2019，59,1634-1644]，提出了两种额外的计算方法来模拟PROTAC介导的三元复杂结构，然后用它们来预测任何伴随的蛋白质降解的效果。方法4B是我们之前的方法之一的扩展，结合了一个特别适合于考虑三元络合物的聚集过程。方法4B在建模的三元复杂合奏中产生了迄今为止最高比例的晶状姿势，在两个案例中接近100%，并且总是给出至少10%的命中率。对于特别麻烦的情况，建议并验证了进一步提高这种性能的技术。通过对新发布的晶体结构进行建模，进一步证实了这种可靠地重现已知晶体三元复杂结构的能力。此外，对于更常见的情况，即三元络合物中间体的结构未知，这项工作中详细说明的方法始终产生可靠地遵循实验蛋白质降解趋势的结果，正如通过七个回溯性案例研究建立的那样。这些不同的案例研究涵盖了具有挑战性的但常见的建模情况，例如当PROTAC结合部分在一个(或两个)蛋白质口袋中的准确取向尚未在实验中建立时。一个PROTAC靶向多个蛋白质，不同PROTAC靶向相同的蛋白质，甚至是E3连接酶对尚未在三元复合体中结构表征的降解，都给出了成功的结果。总体而言，这项工作中详细介绍的计算建模方法应该会极大地促进PROTAC筛选和设计工作，从而使基于PROTAC的退化方法的许多优点能够得到有效利用，并降低成本。
Extending upon our previous publication [Drummond, M.; et al. J. Chem. Inf. Model. 2019, 59, 1634-1644], two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.