ml7b00130_si_001.pdf (2 MB)
Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases
journal contribution
posted on 2017-05-01, 00:00 authored by 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 MobasheryMatrix 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.