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2018 ; 9
(ä): 1382
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English Wikipedia
TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer,
Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In
Silico Search for Small Molecule Binders
#MMPMID29967617
Shaikh F
; He J
; Bhadra P
; Chen X
; Siu SWI
Front Immunol
2018[]; 9
(ä): 1382
PMID29967617
show ga
There is now compelling evidence that TNF receptor type II (TNFR2) is
predominantly expressed on CD4(+)Foxp3(+) regulatory T cells (Tregs) and
myeloid-derived suppressor cells (MDSCs), and plays a major role in the expansion
and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either
antagonists or agonists may represent a novel strategy in the treatment of cancer
and autoimmune diseases, by downregulating or upregulating suppressor cell
activity. The advance in the understanding of complex structure of TNFR2 and its
binding with TNF at molecular levels offers opportunity for structure-guided drug
discovery. This article reviews the current evidences regarding the decisive role
of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort
to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer,
autoimmune diseases, and graft-versus-host disease. To shed light on the
potential TNFR2-targeting small molecules, we for the first time performed
virtual screening of 400,000 natural compounds against the two TNF-binding sites,
regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had
slightly higher docking energies than those at region 3. Nevertheless, free
energy calculation from the TNF-TNFR2 molecular dynamics simulation revealed that
the binding strength of TNF in region 3 is only one-tenth of that in region 4.
This suggests that region 3 is a potentially more viable binding site to be
targeted by small molecules than region 4. Therefore, the effectiveness in
targeting region 3 of TNFR2 deserves further investigation.