Identification of potential MMP-8 inhibitors through virtual screening of natural product databases.

Matrix metalloproteinase-8 (MMP-8), a type II collagenase, is a key enzyme in the degradation of collagens and is implicated in various pathological processes, making it a promising target for drug discovery. Despite advancements in the development of MMP-8 inhibitors, concerns over potential adverse effects persist. This study aims to address these concerns by focusing on the development of novel compounds with improved safety profiles while maintaining efficacy. In this study, we employed a computational approach to screen potent and safe inhibitors of MMP-8 from the Natural Product Activity and Species Source Database (NPASS). Initially, we constructed a pharmacophore model based on the crystal structure of the MMP-8-FIN complex (PDB ID: 4EY6) utilizing the Pharmit tool. This model then guided the selection of 44 promising molecules from NPASS, setting the stage for further analysis and evaluation. We comprehensively evaluated their drug-likeness and toxicity profiles. Molecules 21, 4, and 44 were identified as potentially effective MMP-8 inhibitors through a robust pipeline that included ADMET profiling, molecular docking, and molecular dynamics simulations. Notably, molecule 21 stood out for its low toxicity, high binding stability, and favorable ADMET profile, while molecule 44 demonstrated excellent affinity. These compounds offer structural novelty compared to known MMP-8 inhibitors. These computational results can be combined with in vitro experiments in the future to validate their activity and safety. These findings provide an important reference for drug design of MMP-8 inhibitors.