Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy.

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved in this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are reported as promising novel targets in cancer immunotherapy. IDO1 and TDO overexpression in TNBC cells promote resistance to cell death, proliferation, invasion, and metastasis. To date, there are no clinically available small-molecule inhibitors that target these enzymes. Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility. This situation urges the development of a potent drug-like candidate against these key enzymes. A total of 1574 natural compounds were proclaimed and subjected to ADME screening. Subsequently, the resultant compounds were attributed to hierarchical molecular docking and MM-GBSA validation. Ultimately, re-scoring with the aid of combined machine learning algorithms resulted six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among the lead compounds. In addition, the scaffold analysis also highlighted that the chromanone moiety of the hit compound boasts anti-cancer activity against breast cancer cell lines. The reliability of the results was corroborated through a rigorous 100 ns molecular dynamics simulation using the parameters including RMSD, PCA and FEL analysis. In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC.