From Pharmacophore Models to Lead Compounds: Construction and Activity Evaluation of Novel Indoleamine 2,3-Dioxygenase-1 Inhibitors.

Indoleamine 2,3-dioxygenase-1 (IDO-1), as a crucial immunomodulatory target, plays a pivotal role in regulating immune function. In this study, the ligand-based pharmacophore model (HDAA) and the receptor-based pharmacophore model (HHDA) were respectively constructed, which could comprehensively reflect the spatial distribution characteristics of the core groups of IDO-1 inhibitors. Subsequently, these pharmacophore models were utilized to guide the design of novel IDO-1 inhibitors through a skeleton combination approach. The corresponding molecular structures were synthesized, and evaluated for their biological activities. Notably, compound 7b exhibited highly potent IDO-1 inhibitory activity, which contributed to the body's immune activation in vivo. In summary, the study not only constructed the rational pharmacophore and docking models but also guided the development of novel IDO-1 inhibitor skeletons, providing a promising approach to achieving immune activation.