Department of Chemistry, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Laboratory of Viral Pathogenesis & Infection Prevention and Control, Jinan University, Guangzhou, 510632, China.
Department of Chemistry, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Laboratory of Viral Pathogenesis & Infection Prevention and Control, Jinan University, Guangzhou, 510632, China.
Biomaterials. 2024 Dec;311:122705. doi: 10.1016/j.biomaterials.2024.122705. Epub 2024 Jul 14.
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.
硫氧还蛋白还原酶（TXNRD）的过表达在肿瘤发生中起着关键作用。因此，设计 TXNRD 抑制剂是开发靶向抗癌药物的有前途的策略。然而，选择性差一直是一个挑战，导致临床不可避免的毒性。本文证明了一种开发高选择性手性金属配合物基 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 活性位点内亲电基团之间的兼容性，从而增强了它们的非共价相互作用，从而在确保强抑制作用的基础上，有效避免了源自共价药物相互作用的低选择性。详细的实验和计算结果表明，手性异构体药物与 TXNRD 的活性位点结合，并且手性很好地调节了相互作用强度。特别是，两个大的空间位阻活性基团位于药物相对侧的内消旋构型表现出最高数量的非共价相互作用和对 TXNRD 的最有效抑制。总之，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方法，而且为未来的应用提供了可能的潜在机制的启示。
