PMID- 29670876
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2296-2646 (Print)
IS  - 2296-2646 (Electronic)
IS  - 2296-2646 (Linking)
VI  - 6
DP  - 2018
TI  - Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as 
      TNF-alpha Inhibitors.
PG  - 98
LID - 10.3389/fchem.2018.00098 [doi]
LID - 98
AB  - Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in inflammatory response. 
      Dysregulation of TNF can lead to a variety of disastrous pathological effects, 
      including auto-inflammatory diseases. Antibodies that directly targeting TNF-alpha 
      have been proven effective in suppressing symptoms of these disorders. Compared 
      to protein drugs, small molecule drugs are normally orally available and less 
      expensive. Till now, peptide and small molecule TNF-alpha inhibitors are still in the 
      early stage of development, and much more efforts should be made. In a previously 
      study, we reported a TNF-alpha inhibitor, EJMC-1 with modest activity. Here, we 
      optimized this compound by shape screen and rational design. In the first round, 
      we screened commercial compound library for EJMC-1 analogs based on shape 
      similarity. Out of the 68 compounds tested, 20 compounds showed better binding 
      affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds 
      were tested in cell assay and the most potent compound was 
      2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide (S10) with an IC(50) of 
      14 muM, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of 
      S10 and EJMC-1 binding with TNF-alpha, in the second round, we designed S10 analogs, 
      purchased seven of them, and synthesized seven new compounds. The best compound, 
      4e showed an IC(50)-value of 3 muM in cell assay, which was 14-fold stronger than 
      EJMC-1. 4e was among the most potent TNF-alpha organic compound inhibitors reported 
      so far. Our study demonstrated that 
      2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogs could be 
      developed as potent TNF-alpha inhibitors. 4e can be further optimized for its 
      activity and properties. Our study provides insights into designing small 
      molecule inhibitors directly targeting TNF-alpha and for protein-protein interaction 
      inhibitor design.
FAU - Deng, Xiaobing
AU  - Deng X
AD  - Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
AD  - Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, 
      Peking University, Beijing, China.
FAU - Zhang, Xiaoling
AU  - Zhang X
AD  - Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, 
      Peking University, Beijing, China.
FAU - Tang, Bo
AU  - Tang B
AD  - BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable 
      Species, College of Chemistry and Molecular Engineering, Peking University, 
      Beijing, China.
FAU - Liu, Hongbo
AU  - Liu H
AD  - Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
FAU - Shen, Qi
AU  - Shen Q
AD  - Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, 
      Peking University, Beijing, China.
FAU - Liu, Ying
AU  - Liu Y
AD  - Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, 
      Peking University, Beijing, China.
AD  - BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable 
      Species, College of Chemistry and Molecular Engineering, Peking University, 
      Beijing, China.
FAU - Lai, Luhua
AU  - Lai L
AD  - Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
AD  - Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, 
      Peking University, Beijing, China.
AD  - BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable 
      Species, College of Chemistry and Molecular Engineering, Peking University, 
      Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20180404
PL  - Switzerland
TA  - Front Chem
JT  - Frontiers in chemistry
JID - 101627988
PMC - PMC5893771
OTO - NOTNLM
OT  - TNF-alpha inhibitor
OT  - dihydrobenzo[cd]indole-6-sulfonamide
OT  - structure activity analysis
OT  - synthesis
OT  - virtual screening
EDAT- 2018/04/20 06:00
MHDA- 2018/04/20 06:01
PMCR- 2018/01/01
CRDT- 2018/04/20 06:00
PHST- 2018/01/10 00:00 [received]
PHST- 2018/03/20 00:00 [accepted]
PHST- 2018/04/20 06:00 [entrez]
PHST- 2018/04/20 06:00 [pubmed]
PHST- 2018/04/20 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fchem.2018.00098 [doi]
PST - epublish
SO  - Front Chem. 2018 Apr 4;6:98. doi: 10.3389/fchem.2018.00098. eCollection 2018.