Identification of small molecules that bind to the hemopexin domain of matrix metalloproteinase-9

Abstract

Matrix metalloproteinases (MMPs) play an important role in cancer progression by degrading extracellular matrix components, promoting tumor cell migration, and thus enhancing tumor metastasis. Several generations of anticancer drug were designed to inhibit the proteolytic functions of MMPs, but these drugs failed in clinic trails due to lack of selectivity. This study focused on the hemopexin domain of MMP-9, a nonproteolytic domain, which is essential for MMP-9 regulated tumor cell migration. Compared with the catalytic domain of MMPs, fewer amino acids are conserved between the hemopexin domains of MMP family members. This difference provides the principle basis for identification of inhibitors targeting the hemopexin domain with high selectivity and specificity. An in silico docking approach was employed to screen for novel small-molecule compound that bind to the hemopexin domain of MMP-9. Seven computational hits were evaluated in biochemical binding assays. Of these, 4 compounds were identified that have micromolar affinities for the hemopexin domain of MMP-9