On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations,Journal of Chemical Information and Modeling

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On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-04-10 , DOI: 10.1021/acs.jcim.2c01386
Dahlia R Weiss ₁ , Andrea Bortolato ₂ , Yongnian Sun ₃ , Xianmei Cai ₃ , Chon Lai ₄ , Sixuan Guo ₅ , Lihong Shi ₅ , Veerabahu Shanmugasundaram ₆

Affiliation

Molecular glues are small molecules that simultaneously bind to two proteins, creating a chemically induced protein–protein interface. CELMoDs (cereblon E3 ligase modulators) are a class of molecular glues that promote recruitment of neosubstrate proteins to the E3 ubiquitin ligase cereblon (CRBN) for poly-Lys48-ubiquitination and proteasomal degradation. Ternary complex structures of clinical CELMoDs CC-885 and CC-90009 bound to CRBN and neosubstrate G1 to S phase transition protein 1 (GSPT1) have been experimentally determined. Although cellular degradation is a downstream event, dependent not only on the affinity of the glue CELMoD in the ternary complex, we test the applicability of established structure-based drug design principles to predict binding affinity of CELMoDs to the protein–protein neointerface and correlation to measured cellular degradation for the neosubstrates GSPT1 and zinc finger Aiolos (IKZF3). For a congeneric series of CELMoDs, which have a similar sequence of binding events and resultant binding modes, we conclude that well-established structure-based methods that measure in silico ternary complex stabilities can predict relative degradation potency by CELMoDs.

中文翻译：

关于蛋白质降解中的三元复合物稳定性：计算机模拟分子胶结合亲和力计算

分子胶是同时结合两种蛋白质的小分子，形成化学诱导的蛋白质-蛋白质界面。CELMoDs（cereblon E3 连接酶调节剂）是一类分子胶，可促进新底物蛋白募集到 E3 泛素连接酶 cereblon (CRBN)，以进行聚-Lys48-泛素化和蛋白酶体降解。临床 CELMoDs CC-885 和 CC-90009 与 CRBN 和新底物 G1 到 S 相变蛋白 1 (GSPT1) 结合的三元复杂结构已通过实验确定。尽管细胞降解是一个下游事件，不仅取决于胶水 CELMoD 在三元复合物中的亲和力，我们测试了已建立的基于结构的药物设计原则的适用性，以预测 CELMoD 对蛋白质-蛋白质新界面的结合亲和力以及与新底物 GSPT1 和锌指 Aiolos (IKZF3) 的测量细胞降解的相关性。对于一系列具有相似结合事件序列和合成结合模式的 CELMoD，我们得出结论，基于结构的成熟方法测量计算机三元复合物的稳定性可以预测 CELMoD 的相对降解效力。

更新日期：2023-04-10

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