Chirality-driven strong thioredoxin reductase inhibition

手性(物理) 材料科学 硫氧还蛋白还原酶 硫氧还蛋白 纳米技术 生物物理学 生物化学 生物 物理 粒子物理学 夸克 Nambu–Jona Lasinio模型 手征对称破缺
作者
Mingkai Chen,Junping Wang,Fei Cai,Junxian Guo,Xiaoyu Qin,Shouxin Zhang,Tianfeng Chen,Li Ma
出处
期刊:Biomaterials [Elsevier BV]
卷期号:311: 122705-122705
标识
DOI:10.1016/j.biomaterials.2024.122705
摘要

Overexpression of thioredoxin reductase (TXNRD) plays crucial role in tumorigenesis. Therefore, designing TXNRD inhibitors is a promising strategy for targeted anticancer drug development. However, poor selectivity has always been a challenge, resulting in unavoidable toxicity in clinic. Herein we demonstrate a strategy to develop highly selective chiral metal complexes-based TXNRD inhibitors. By manipulating the conformation of two distinct weakly interacting groups, we optimize the compatibility between the drug and the electrophilic group within the active site of TXNRD to enhance their non-covalent interaction, thus effectively avoids the poor selectivity deriving from covalent drug interaction, on the basis of ensuring the strong inhibition. Detailed experimental and computational results demonstrate that the chiral isomeric drugs bind to the active site of TXNRD, and the interaction strength is well modulated by chirality. Especially, the meso-configuration, in which the two large sterically hindered active groups are positioned on opposite sides of the drug, exhibits the highest number of non-covalent interactions and most effective inhibition on TXNRD. Taken together, this work not only provides a novel approach for developing highly selective proteinase inhibitors, but also sheds light on possible underlying mechanisms for future application.
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