Structure-based discovery of a new type of scaffold compound as binding competitors for protein-bound Uremic Toxins.

Protein-bound uremic toxins (PBUTs) are the main cause of uremia, but traditional hemodialysis is ineffective in removing them because of their strong ability to bind to human serum albumin (HSA), highlighting the need for new treatments. In this study, first, structure-based docking was used to screen a diverse library of 200,376 virtual compounds against the active sites I and II. After two rounds of docking screening, 3944 candidate molecules were obtained. Second, 23 candidate molecules were obtained after ADMET prediction and toxicity analysis. Five candidate molecules were finally obtained after visual analysis and MM-PBSA calculations. We subsequently assessed their competitive displacement efficiency through a microdialysis experiment, and the results revealed that ZINC000008791789, ZINC000012297018, and ZINC000012296493 are promising binding competitors for PBUTs, as they have higher dialysis efficiency than the optimal displacer LA, approximately double the dialysis efficiency. The other two molecules, ZINC000031161007 and ZINC000004090361, although less efficient than LA, still outperformed the control group. Notably, four of them shared the same molecular scaffold, and three of them contained a flavonoid group. These findings provide a foundation for the development of more effective PBUT binding competitors, potentially benefiting uremia patients in the future.