Discovery and Molecular Docking of an SLC29A1 Inhibitor

The equilibrative nucleoside transporter 1 (ENT1/SLC29A1) plays a critical role in cellular nucleoside homeostasis and has emerged as a promising therapeutic target for cancer, cardiovascular diseases, and metabolic disorders. This study employed molecular docking techniques to identify and characterize novel SLC29A1 inhibitors using the high-resolution crystal structure of hENT1 (PDB ID: 6OB6). Four candidate compounds (C27-F, C27-E9, C27-E9.1, and C27-E9.2) were evaluated for their binding interactions, revealing strong affinities to key residues (Gly154, Trp29) and transmembrane domains (TM1, TM7, TM9) involved in nucleoside transport. Among these, C27-E9.2 exhibited the highest docking score, suggesting superior inhibitory potential by mimicking the steric occlusion mechanism of established inhibitors like dilazep and NBMPR. The findings highlight the therapeutic promise of these compounds in modulating hENT1 activity, particularly in overcoming gemcitabine resistance in pancreatic cancer and enhancing adenosine-mediated cardioprotection. However, further experimental validation is required to confirm their efficacy and pharmacokinetic suitability. This study not only advances the development of targeted hENT1 inhibitors but also contributes to the broader understanding of solute carrier (SLC) transporters as druggable targets, paving the way for precision medicine applications in oncology and beyond.