当前位置: X-MOL 学术Org. Biomol. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Mechanistic insights into lysine-targeting covalent inhibition through a theoretical study of ester aminolysis
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2021-11-03 , DOI: 10.1039/d1ob01963e
Volkan Fındık 1, 2 , Manuel F Ruiz-López 1 , Safiye Sag Erdem 2
Affiliation  

Development of targeted covalent inhibitors in drug design has a broad and important interest and many efforts are currently being made in this direction. Targeted covalent inhibitors have special relevance in oncology due to the possibilities they offer to overcome the problems of acquired resistance. In recent experiments, lysine-targeting has been envisaged for the irreversible inhibition of the heterodimeric lipid kinase phosphoinositide 3-kinase delta (PI3Kδ). Activated esters have been evaluated and shown to be promising inhibitors of this enzyme, but the reaction mechanisms display specificities that are not yet fully understood. In the present work, we have carried out a theoretical study of the aminolysis reaction of model esters in aqueous solution to gain insights into the corresponding biological processes. We have found that phenolic esters bearing electron-withdrawing groups are particularly reactive. The predicted mechanism involves the formation of a tetrahedral zwitterionic intermediate, which dissociates into an alkoxide and a protonated amide, this charge separation being the driving force for the subsequent proton transfer and final product formation. Structure–reactivity relationships are reported and shown to be a useful tool for evaluating potential inhibitor candidates.

中文翻译:

通过酯氨解的理论研究对赖氨酸靶向共价抑制的机理见解

在药物设计中开发靶向共价抑制剂具有广泛而重要的兴趣,目前正朝着这个方向做出许多努力。靶向共价抑制剂在肿瘤学中具有特殊的相关性,因为它们提供了克服获得性耐药问题的可能性。在最近的实验中,赖氨酸靶向被设想用于不可逆地抑制异二聚体脂质激酶磷酸肌醇 3-激酶δ(PI3Kδ)。已对活化酯进行了评估,并显示它们是这种酶的有希望的抑制剂,但反应机制显示出尚未完全了解的特异性。在目前的工作中,我们对模型酯在水溶液中的氨解反应进行了理论研究,以深入了解相应的生物过程。我们发现带有吸电子基团的酚酯特别具有反应性。预测的机制涉及形成四面体两性离子中间体,该中间体解离成醇盐和质子化酰胺,这种电荷分离是随后质子转移和最终产物形成的驱动力。结构-反应性关系被报道并被证明是评估潜在抑制剂候选物的有用工具。
更新日期:2021-11-10
down
wechat
bug