Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

Li Juan Liu, Ka Ho Leung, Sheng Lin, Daniel Shiu Hin Chan, Dewi Susanti, Weidong Rao, Philip Wai Hong Chan*, Edmond Dik Lung MA, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds, from which compound 1 emerged as a top candidate. In a cell-free assay, compound 1 inhibited TACE enzymatic activity in a dose-dependent manner. Moreover, compound 1 inhibited the production of soluble TNF-α in human acute monocytic leukemia THP-1 cells without impacting nitric oxide production, and exhibited anti-proliferative activity against THP-1 cells. We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors. This study also validates the use of pharmacophore modeling to identify enzyme inhibitors.

Original languageEnglish
Pages (from-to)92-97
Number of pages6
JournalMethods
Volume71
Issue numberC
DOIs
Publication statusPublished - 2015

Scopus Subject Areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • Inhibitor
  • Pharmacophore
  • TACE
  • Tumor necrosis factor
  • Virtual screening

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