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

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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 languageEnglish (US)
Pages (from-to)654-659
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number6
DOIs
StatePublished - Jun 8 2017

Keywords

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

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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