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

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.

• Authors: Li-Juan Liu, Ka-Ho Leung, Sheng Lin, Daniel Shiu-Hin Chan, Dewi Susanti, Weidong Rao, Philip Wai Hong Chan, Dik-Lung Ma, Chung-Hang Leung
• Journal: Methods (San Diego, Calif.) (Methods) Vol. 71 Pg. 92-7 (Jan 2015) ISSN: 1095-9130 [Electronic] United States
• PMID: 25260600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM Proteins (antagonists & inhibitors, chemistry)
• ADAM17 Protein
• Cell Line, Tumor
• Computer Simulation
• Databases, Chemical
• Drug Discovery (methods)
• Humans
• Models, Molecular