Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors
| Autor: | Qiang Xu, Yisheng Lai, Ge Shushan, Wen Liu, Zheng Yingbo, Li Yuezhen, Yihua Zhang, Yi Zou, Wenjie Guo, Yue Hu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_treatment
In silico Drug Evaluation Preclinical Antineoplastic Agents Computational biology 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Cancer immunotherapy Dioxygenase Drug Discovery medicine Tumor Cells Cultured Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Hemeproteins Heme 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Virtual screening Mice Inbred BALB C Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry General Medicine Small molecule 0104 chemical sciences Hydrazines Colonic Neoplasms Pharmacophore Drug Screening Assays Antitumor HeLa Cells |
| Zdroj: | European journal of medicinal chemistry. 184 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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