Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases

Kiran V. Mahasenan; Maria Bastian; Ming Gao; Emma Frost; Derong Ding; Katerina Zorina-Lichtenwalter; John Jacobs; Mark A. Suckow; Valerie A. Schroeder; William R. Wolter; Mayland Chang; Shahriar Mobashery

doi:10.1021/acsmedchemlett.7b00130

Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases

Kiran V. Mahasenan, Maria Bastian, Ming Gao, Emma Frost, Derong Ding, Katerina Zorina-Lichtenwalter, John Jacobs, Mark A. Suckow, Valerie A. Schroeder, William R. Wolter, Mayland Chang, Shahriar Mobashery

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.

Original language	English
Pages (from-to)	654-659
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00130
State	Published - Jun 8 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

Animal studies
Enzyme kinetics
Matrix metalloproteinases
Molecular docking
Molecular dynamics
Virtual library design

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.7b00130

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Mahasenan, K. V., Bastian, M., Gao, M., Frost, E., Ding, D., Zorina-Lichtenwalter, K., Jacobs, J., Suckow, M. A., Schroeder, V. A., Wolter, W. R., Chang, M., & Mobashery, S. (2017). Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases. ACS Medicinal Chemistry Letters, 8(6), 654-659. https://doi.org/10.1021/acsmedchemlett.7b00130

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title = "Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases",

abstract = "Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.",

keywords = "Animal studies, Enzyme kinetics, Matrix metalloproteinases, Molecular docking, Molecular dynamics, Virtual library design",

author = "Mahasenan, {Kiran V.} and Maria Bastian and Ming Gao and Emma Frost and Derong Ding and Katerina Zorina-Lichtenwalter and John Jacobs and Suckow, {Mark A.} and Schroeder, {Valerie A.} and Wolter, {William R.} and Mayland Chang and Shahriar Mobashery",

note = "Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = jun,

day = "8",

doi = "10.1021/acsmedchemlett.7b00130",

language = "English",

volume = "8",

pages = "654--659",

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Mahasenan, KV, Bastian, M, Gao, M, Frost, E, Ding, D, Zorina-Lichtenwalter, K, Jacobs, J, Suckow, MA, Schroeder, VA, Wolter, WR, Chang, M & Mobashery, S 2017, 'Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases', ACS Medicinal Chemistry Letters, vol. 8, no. 6, pp. 654-659. https://doi.org/10.1021/acsmedchemlett.7b00130

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T1 - Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases

AU - Mahasenan, Kiran V.

AU - Bastian, Maria

AU - Gao, Ming

AU - Frost, Emma

AU - Ding, Derong

AU - Zorina-Lichtenwalter, Katerina

AU - Jacobs, John

AU - Suckow, Mark A.

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Chang, Mayland

AU - Mobashery, Shahriar

PY - 2017/6/8

Y1 - 2017/6/8

N2 - Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.

AB - Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.

KW - Animal studies

KW - Enzyme kinetics

KW - Matrix metalloproteinases

KW - Molecular docking

KW - Molecular dynamics

KW - Virtual library design

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Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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