Document Type

Journal Article

Department/Unit

Department of Chemistry

Title

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

Language

English

Abstract

© 2014 Elsevier Inc.. 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.

Keywords

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

Publication Date

2015

Source Publication Title

Methods

Volume

71

Start Page

92

End Page

97

Publisher

Elsevier

DOI

10.1016/j.ymeth.2014.09.005

Link to Publisher's Edition

http://dx.doi.org/10.1016/j.ymeth.2014.09.005

ISSN (print)

10462023

ISSN (electronic)

10959130

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