Computational study of effective matrix metalloproteinase 9 (MMP9) targeting natural inhibitors.

Liu, Naimeng; Wang, Xinhui; Wu, Hao; Lv, Xiaye; Xie, Haoqun; Guo, Zhen; Wang, Jing; Dou, Gaojing; Zhang, Chenxi; Sun, Mindan

OBJECT The present study screened ideal lead natural compounds that could target and inhibit matrix metalloproteinase 9 (MMP9) protein from the ZINC database to develop drugs for clear cell renal cell carcinoma (CCRCC)-targeted treatment. METHODS Discovery Studio 4.5 was used to compare and screen the ligands with the reference drug, solasodine, to identify ideal candidate compounds that could inhibit MMP9. The LibDock module was used to analyze compounds that could strongly bind to MMP9, and the top 20 compounds determined by the LibDock score were selected for further research. ADME and TOPKAT modules were used to choose the safe compounds from these 20 compounds. The selected compounds were analyzed using the CDOCKER module for molecular docking and feature mapping for pharmacophore prediction. The stability of these compound-MMP9 complexes was analyzed by molecular dynamic simulation. Cell counting kit-8, colony-forming, and scratch assays were used to analyze the anti-CCRCC effects of these ligands. RESULTS Strong binding to MMP9 was exhibited by 6,762 ligands. Among the top 20 compounds, sappanol and sventenin exhibited nearly undefined blood-brain barrier level and lower aqueous solubility, carcinogenicity, and hepatotoxicity than the positive control drug, solasodine. Additionally, these compounds exhibited lower potential energies with MMP9, and the ligand-MMP9 complexes were stable in the natural environment. Furthermore, sappanol inhibited CCRCC cell migration and proliferation. CONCLUSION Sappanol and sventenin are safe and reliable compounds to target and inhibit MMP9. Sappanol can CCRCC cell migration and proliferation. These two compounds may give new thought to the targeted therapy for patients with CCRCC.