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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
Shaikh, Faraz1; He, Jiang2; Bhadra, Pratiti1; Chen, Xin2; Siu, Shirley W., I1
2018-06-18
Source PublicationFRONTIERS IN IMMUNOLOGY
ISSN1664-3224
Volume9
Abstract

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.

KeywordTnf Receptor Type Ii Tnf Regulatory t Cells Virtual Screening Drug Discovery Mm-pbsa
DOIhttp://doi.org/10.3389/fimmu.2018.01382
URLView the original
Indexed BySCI
Language英语
WOS Research AreaImmunology
WOS SubjectImmunology
WOS IDWOS:000435495900002
PublisherFRONTIERS MEDIA SA
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorChen, Xin; Siu, Shirley W., I
Affiliation1.Department of Computer and Information Science, Faculty of Science and Technology, University of Macau, Macao, China
2.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
First Author AffilicationFaculty of Science and Technology
Corresponding Author AffilicationInstitute of Chinese Medical Sciences;  Faculty of Science and Technology
Recommended Citation
GB/T 7714
Shaikh, Faraz,He, Jiang,Bhadra, Pratiti,et al. 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[J]. FRONTIERS IN IMMUNOLOGY,2018,9.
APA Shaikh, Faraz,He, Jiang,Bhadra, Pratiti,Chen, Xin,&Siu, Shirley W., I.(2018).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.FRONTIERS IN IMMUNOLOGY,9.
MLA Shaikh, Faraz,et al."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".FRONTIERS IN IMMUNOLOGY 9(2018).
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