Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors.

Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors. Eur J Med Chem. 2019 Oct 03;184:111750 Authors: Zou Y, Hu Y, Ge S, Zheng Y, Li Y, Liu W, Guo W, Zhang Y, Xu Q, Lai Y Abstract Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe. PMID: 31610376 [PubMed - as supplied by publisher]
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research