Abstract：
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.
摘要：
硫氧还蛋白还原酶（TXNRD）的过表达在肿瘤发生中起着至关重要的作用。因此,设计TXNRD抑制剂是靶向抗癌药物开发的有前景的策略。然而,选择性差一直是一个挑战，导致临床上不可避免的毒性。在本文中,我们展示了开发基于高选择性手性金属络合物的TXNRD抑制剂的策略。通过操纵两个不同的弱相互作用基团的构象，我们优化了药物与TXNRD活性位点内的亲电子基团之间的相容性，以增强它们的非共价相互作用，从而有效地避免了共价药物相互作用产生的选择性差，在保证强抑制的基础上。详细的实验和计算结果表明，手性异构药物与TXNRD的活性位点结合，相互作用强度受到手性很好的调节。尤其是,介观构型，其中两个大的空间位阻活性基团位于药物的相对侧，表现出最高数量的非共价相互作用和对TXNRD的最有效抑制。一起来看,这项工作不仅为开发高选择性蛋白酶抑制剂提供了一种新的方法，但也揭示了未来应用的潜在机制。
