Novel insights into structure–activity relationships of kynurenine 3-monooxygenase inhibitors (KMOis) with emphasis on chemical space, activity landscape exploration

Kynurenine 3-monooxygenase (KMO) is a pivotal target in the kynurenine pathway (KP). KMO inhibitors (KMOis) decrease neurotoxic metabolites like 3-hydroxykynurenine and quinolinic acid while increasing neuroprotective kynurenic acid levels. It offers a promising therapeutic approach for treating neurodegenerative diseases, psychiatric disorders, acute pancreatitis, and immune-mediated conditions. The authors provide an overview of the biology and function of KMO and highlight the key evidence for KMOi design. The authors also provide a summary of the structure - activity relationships (SARs) of several series of KMOis based on a comprehensive search of literature utilizing PubMed, Google Scholar, and Scopus, covering the period between 2015 and 2025. This works also provides explicit coverage to the chemical space of human KMOis (hKMOis), thereby providing a novel framework for the rational design of next-generation therapeutics targeting this enzyme. The KP, particularly KMO, has emerged as a compelling target for drug discovery. The Structure-Similarity Activity Trailing (SimilACTrail) map of hKMOis has provided novel insights for mapping the molecular landscape of hKMOis. A high scaffold-hopping rate (40.24%) underscores the potential for chemical innovation, while the identification of activity cliffs (0.58%) provides critical data for refining SARs. These findings offer a promising avenue for therapeutic development, with opportunities for the optimization of chemical scaffolds.