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2018 ; 9
(ä): 277
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Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through
Structure-Based Virtual Screening
#MMPMID29651242
Zhang G
; Xing J
; Wang Y
; Wang L
; Ye Y
; Lu D
; Zhao J
; Luo X
; Zheng M
; Yan S
Front Pharmacol
2018[]; 9
(ä): 277
PMID29651242
show ga
Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric
heme-containing enzyme that catalyzes the first and the rate limiting step in
catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a
significant role in the proliferation and differentiation of T cells. IDO1 has
been proven to be an attractive target for anticancer therapy and chronic viral
infections. In the present study, a class of IDO1 inhibitors with novel scaffolds
were identified by virtual screening and biochemical validation, in which the
compound DC-I028 shows moderate IDO1 inhibitory activity with an IC(50) of 21.61
?M on enzymatic level and 89.11 ?M on HeLa cell. In the following hit expansion
stage, DC-I02806, an analog of DC-I028, showed better inhibitory activity with
IC(50) about 18 ?M on both enzymatic level and cellular level. The
structure-activity relationship (SAR) of DC-I028 and its analogs was then
discussed based on the molecular docking result. The novel IDO1 inhibitors of
DC-I028 and its analogs may provide useful clues for IDO1 inhibitor development.