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; Dik Lung Ma; Chung Hang Leung

doi:10.1016/j.ymeth.2014.09.005

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^*, Dik Lung Ma, Chung Hang Leung

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-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 language	English
Pages (from-to)	92-97
Number of pages	6
Journal	Methods
Volume	71
Issue number	C
DOIs	https://doi.org/10.1016/j.ymeth.2014.09.005
Publication status	Published - 2015

Scopus Subject Areas

Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

Inhibitor
Pharmacophore
TACE
Tumor necrosis factor
Virtual screening

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymeth.2014.09.005

Cite this

@article{1611cc07b7a14b3aaad811fe196ddef1,

title = "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.",

keywords = "Inhibitor, Pharmacophore, TACE, Tumor necrosis factor, Virtual screening",

author = "Liu, {Li Juan} and Leung, {Ka Ho} and Sheng Lin and Chan, {Daniel Shiu Hin} and Dewi Susanti and Weidong Rao and Chan, {Philip Wai Hong} and Ma, {Dik Lung} and Leung, {Chung Hang}",

note = "Funding Information: This work is supported by Hong Kong Baptist University - Hong Kong ( FRG2/12-13/021 and FRG2/13-14/008 ), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund ( HMRF/13121482 ), the Research Grants Council ( HKBU/201811 , HKBU/204612 , and HKBU/201913 ), the French National Research Agency/Research Grants Council Joint Research Scheme ( A-HKBU201/12 ), the Science and Technology Development Fund - Macau, Macao SAR ( 103/2012/A3 ) and the University of Macau ( MYRG091(Y3-L2)-ICMS12-LCH , MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS ), and University Research Committee Grant ( RG55/06 ) from Nanyang Technological University - Singapore and a Science and Engineering Research Council Grant ( 092 101 0053 ) from A∗STAR - Singapore. ",

year = "2015",

doi = "10.1016/j.ymeth.2014.09.005",

language = "English",

volume = "71",

pages = "92--97",

journal = "Methods",

issn = "1046-2023",

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T1 - Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

AU - Liu, Li Juan

AU - Leung, Ka Ho

AU - Lin, Sheng

AU - Chan, Daniel Shiu Hin

AU - Susanti, Dewi

AU - Rao, Weidong

AU - Chan, Philip Wai Hong

AU - Ma, Dik Lung

AU - Leung, Chung Hang

N1 - Funding Information: This work is supported by Hong Kong Baptist University - Hong Kong ( FRG2/12-13/021 and FRG2/13-14/008 ), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund ( HMRF/13121482 ), the Research Grants Council ( HKBU/201811 , HKBU/204612 , and HKBU/201913 ), the French National Research Agency/Research Grants Council Joint Research Scheme ( A-HKBU201/12 ), the Science and Technology Development Fund - Macau, Macao SAR ( 103/2012/A3 ) and the University of Macau ( MYRG091(Y3-L2)-ICMS12-LCH , MYRG121(Y3-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS ), and University Research Committee Grant ( RG55/06 ) from Nanyang Technological University - Singapore and a Science and Engineering Research Council Grant ( 092 101 0053 ) from A∗STAR - Singapore.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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JO - Methods

JF - Methods

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ER -

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

Abstract

Scopus Subject Areas

User-Defined Keywords

UN SDGs

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