Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1′ pocket and their quantitative structure-activity relationship (QSAR) study

Jee Sun Yang, Kwangwoo Chun, Jung Eun Park, Misun Cho, Jeongjea Seo, Doona Song, Hongchul Yoon, Chun Ho Park, Bo Young Joe, Jong Hee Choi, Myung Hwa Kim, Gyoonhee Han

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A series of coumarin based TACE inhibitors were designed to bind in S1′ pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1′ pocket and the TACE inhibitory activity well.

Original languageEnglish
Pages (from-to)8618-8629
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number24
DOIs
Publication statusPublished - 2010 Dec 15

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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