Discovery of novel potential small-molecule inhibitors of MMP-9 based on a pharmacophore virtual screening strategy

Matrix metalloproteinases (MMPs) are a class of calcium-dependent, zinc-containing endopeptidases involved in several cellular processes. MMP-9, among MMP isoforms, drives tumor invasion, rheumatoid arthritis, and osteoarthritis via extracellular matrix degradation in the tumor microenvironment and cartilage, and by promoting angiogenesis. Although progress has been made in the development of MMP-9 inhibitors, concerns about their potential side effects still exist. This study aimed to identify safe and effective candidate inhibitors of MMP-9. In this study, computational methods were employed to identify effective and safe MMP-9 inhibitors from the ZINC database. Initially, a pharmacophore model was formulated based on the crystal structure of the MMP-9 complex (PDB ID: 5I12 ) using the Pharmit tool. This model was subsequently used to screen 70 promising molecules from the ZINC database. Comprehensive analyses, including ADMET prediction, molecular docking, and molecular dynamics simulations, were conducted to evaluate the drug properties, binding affinity, and stability of these compounds. The screening process identified five molecules with the potential to serve as effective MMP-9 inhibitors. These compounds exhibited excellent drug properties and lower toxicity. They demonstrated strong interactions with the active site residues, high binding affinity, and minimal fluctuations in the protein structure, forming compact complexes. Notably, ZINC1069371 showed a higher dissociation tendency and lower toxicity compared to other candidates. Additionally, these compounds exhibited structural novelty compared to known MMP-9 inhibitors. This study has identified five novel small-molecule inhibitors of MMP-9. These findings can be further validated through in vitro experiments to confirm their activity and safety.