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
10.1021/acsmedchemlett.7b00130.s001
https://acs.figshare.com/articles/journal_contribution/Exploitation_of_Conformational_Dynamics_in_Imparting_Selective_Inhibition_for_Related_Matrix_Metalloproteinases/4964759
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 <i>in silico</i> 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.
2017-05-01 00:00:00
Conformational Dynamics
enzyme families
benzoxazinone
function
molecular-dynamics information
Related Matrix Metalloproteinases Matrix metalloproteinases
site
silico library
MMP