Identification of a Novel Core Structure of Apo-Ido1 Inhibitors Through Virtual Screening and Preliminary Hit Optimization

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme considered as a potential therapeutic target for neurodegenerative diseases and cancer. However, the further development of traditional IDO1 inhibitors has been hindered by their limited clinical efficacy. Recently, type IV apo-IDO1 inhibitors offer a new strategy for developing IDO1 inhibitors due to their highly selective and durable inhibition. In this study, we developed a virtual screening (VS) workflow to identify novel apo-IDO1 inhibitors. A hit compound MQ-1 (IC₅₀ = 1.29 μM) was identified by molecular docking and binding pose metadynamics (BPMD). Biological evaluations confirmed that MQ-1 selectively targets apo-IDO1 and disrupts heme binding. To optimize the structure of MQ-1, free energy landscape was constructed, and the dissociation mechanism was explored by random accelerated molecular dynamics and self-organizing maps. Finally, several MQ-1 analogs with improved inhibitory activity were discovered, such as MQ-1a (IC₅₀ = 1.03 μM), MQ-1e (IC₅₀ = 0.81 μM), and MQ-1n (IC₅₀ = 0.29 μM). The established VS workflow effectively applied to IDO1 and can also be applied to similar targets. The novel apo-IDO1 inhibitor core structure provides a starting point for potential antitumor drug development.