Structure-Based Design of Potent and Selective Inhibitors for Stromelysin-1 and Mr1-MMP

摘要

Matrix metalloproteinases (MMPs) represent an important class of therapeutic targets for the treatment of diseases such as cancer. MMPs play a physiological role in the degradation of structural extra-cellular matrix (ECM) proteins and thus promote angiogenesis, a condition necessary for sustained tumor growth. Consequently, the inhibition of MMP enzymes may serve as disease- modifying agents by preventing ECM degradation and angiogenesis, and ultimately act as anti-cancer agents. In this research, we have used structure-based drug design methodologies to model selective biological inhibitors for MMPs implicated in breast cancer. Specifically, we are developing, refining, and validating computational protocols and simulations methods for docking and molecular dynamics simulations. The focus has been on validating the parameters used for molecular modeling through (1) computation of free energies of hydration, (2) flexible docking studies, and (3) evaluating Molecular Mechanics Poisson-Boltzmann Surface Area methods for computation of binding affinities. Structure-based design targeting specific MMPs will benefit from these studies by improving the accuracy of predicted binding modes and affinities of anti- breast cancer inhibitors prior to purchase or synthesis.