Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization
Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization
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DOI：
10.1002/chem.202001608
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发表时间：
2020-05-11
影响因子：
4.3
通讯作者：
O'Mahony, Gavin
中科院分区：
文献类型：
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作者：
Bosica, Francesco;Andrei, Sebastian A.;O'Mahony, Gavin
14-3-3蛋白质的蛋白质-蛋白质相互作用（PPI）是研究PPI稳定性的模型系统。复杂的天然产物Fusicoccin A稳定了许多14-3-3 PPI，但不适合用于SAR研究，这促使人们寻找更多的药物样化学物质。然而，能够进行此类研究的药物样14-3-3 PPI稳定剂仍然难以捉摸。PPI与极低效力稳定剂复合的X射线晶体结构揭示了意想不到的非蛋白质相互作用的配体螯合的Mg 2+，导致发现金属离子依赖性14-3-3 PPI稳定效力。这源于一种新的螯合控制的生物活性构象稳定效应。金属螯合作用与泛测定干扰化合物（PAINS）和频繁的击球行为有关，但螯合作用显然也可以导致真正的效力增加，并可用作指导化合物优化的药物化学策略。为了证明这一点，我们利用这一效应设计了第一个有效的、选择性的和药物样的14-3-3 PPI稳定剂。
Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg2+ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.