Structure-Based Design of Potent and Selective Inhibitors for Stromelysin-1 and Mt1-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 are using structure-based drug design methodologies in the hopes of finding novel and selective biological inhibitors for MMPs. Specifically, we are developing, refining, and validating the computational protocols and simulations methods used to model MMPs. The focus is on (1) validating the force field parameter sets used in the docking studies by comparing the calculated results with experimental MMP-inhibitor crystal structures, and (2) evaluating which scoring functions are most accurate for estimating MMP affinities. Structure-based design targeting specific MMPs will benefit from these studies by improving the accuracy of predicted binding modes and affinities of compounds prior to purchase or synthesis.