Discovery Of Novel Indoleamine 2,3-dioxygenase 1(IDO1) Inhibitors Via High Throughput Virtual Screening,Biology Validation And Resythesis

Cancer is one of the most serious diseases,which threatens health and safety of human.Tumor-escape is a hallmark of cancers,which brings many difficulties and troubles in the cancer therapy.Indoleamine 2,3 –dioxygense1(IDO1)is the initial and rate-limiting enzyme and in the kynuernine pathway.Kynuernine pathway is reported to have close correlation with tumor-escape and IDO1 is proved to emerge as a promising target for cancer immunotherapy.The activity of cancers were suppressed when inhibor the IDO1.Apart from tumor-escape,IDO1 is the target for Alzheimer's disease and melancholia.The number of IDO1 inhibitors remain very few.Obviously,the discovery of novel indoleamine 2,3-dioxygense 1 inhibitors is bright and encouraging.Computer aided drug design play an important role in discovery,design and optimization of drugs.High throughput virtual screening is an effective,rapid and inexpensive tool to search for novel lead compounds.To here,a virtual screening cascade protocol,combining both pharmacophore modeling,molecular docking,ADMET prediction and Lipinski's Rule of Five,was employed to query commercial database ZINC.Finally,23 compounds was purchased and tested in vitro IDO1 inhibitory activity assay.5 compounds exhibit greater than 20% inhibition at a test concentration of 10 ?M,with two compounds having an IC50 value of 23.8 and 8.8 ?M.The activity of two compound was much more the most commonly used inhibitor 1-MT.The result of activity assay proved that our protocol was effective and maybe be adapted elsewhere.Two compounds with nove scaffold have the potential to be lead compounds after some modifiction and optimization.We sucessfully designed a high yield scheme and sythesized hit15,which laid some foundation on the future chemistry elaboration of hit15.