论文标题
由螯合控制的生物活性构象指导的药物样蛋白质 - 蛋白质相互作用稳定剂的设计
Design Of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization
论文作者
论文摘要
14-3-3蛋白的蛋白质蛋白相互作用（PPI）是研究PPI稳定的模型系统。复杂的天然产物fusicoccin A稳定了许多14-3-3的PPI，但不适合用于SAR研究，激励人们寻找更多类似药物的化学物质。然而，使该研究能够像药物一样的14-3-3 PPI稳定剂仍然难以捉摸。 PPI的X射线晶体结构具有极低的效力稳定剂，发现了意外的非蛋白质相互作用，配体含有的Mg 2+，从而发现了金属离子依赖性的14-3-3 PPI稳定效力。这起源于一种新型的螯合控制生物活性构象稳定效应。金属螯合已与泛 - 测定干扰化合物（疼痛）和频繁的击球手行为相关，但螯合显然也可以导致真正的效力提高，并找到用作指导化合物优化的药物化学策略。为了证明这一点，我们利用了效果来设计第一个有效，选择性和类似药物的14-3-3 PPI稳定剂。
The 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 study 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 Mg 2+ 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.
