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

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 benzoxazino...

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Veröffentlicht in:ACS medicinal chemistry letters 2017-06, Vol.8 (6), p.654-659
Hauptverfasser: Mahasenan, Kiran V, Bastian, Maria, Gao, Ming, Frost, Emma, Ding, Derong, Zorina-Lichtenwalter, Katerina, Jacobs, John, Suckow, Mark A, Schroeder, Valerie A, Wolter, William R, Chang, Mayland, Mobashery, Shahriar
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Sprache:eng
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Zusammenfassung: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00130