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

Abstract

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.

The Inhibitors of CDK4/6 from a Library of Marine Compound Database: A Pharmacophore, ADMET, Molecular Docking and Molecular Dynamics Study

“…The blood–brain barrier permeability (BBB), water solubility, intestinal absorbance, hepatotoxicity and CYP2D6 enzyme inhibition descriptors of the drug were predicted. The blood–brain barrier permeability of all compounds was predicted to be “undefined”, indicating that the blood–brain barrier permeability of all 20 compounds was outside of the 99% confidence ellipse [ 30 ]. Except for the blood–brain barrier permeability of the drug not being successfully predicted, the rest of the properties were described in a numerical or hierarchical manner.…”

“…The closer the X-axis is to zero, the higher the accuracy; the Y-axis of the vertical coordinate is called sensitivity, also known as the true positive rate (sensitivity), and the larger the Y-axis is, the higher the accuracy, as reflected by the area under the ROC curve (AUC) being closer to 1 [ 39 ]. The pharmacophore ranking score given by the platform was also considered, and the pharmacophore with both the optimal ranking score and the area under the ROC curve (AUC) value was selected as the next step in the virtual screening [ 30 ]. The structures of all inhibitor and decoy molecules are shown in Figure S2 and Table S1 of the Supplementary Material .…”

Apple Derived Exosomes Improve Collagen Type I Production and Decrease MMPs during Aging of the Skin through Downregulation of the NF-κB Pathway as Mode of Action

“…Metalloproteinase 1 and 8 both target interstitial collagen type I, II and III, while Metalloproteinase 9 is specialized in collagen type IV and V. Thus, together they would be able to break down and remodel the ECM with significant changes. Furthermore, MMPs have a part in other pathophysiological processes; particularly, MMP9 is considered a cancer biomarker [ 63 , 64 ].…”

Prediction of MMP-9 Polymorphism Impacts on MDR-TB by Molecular Simulation and Network Interaction

“…They also liberate bio-active proteins, including cytokines, chemokines, and growth factors. 4 Additionally, MMP-9 can degrade type IV collagen and destroy the basement lung membrane. Several studies have exhibited the crucial role of MMP-9 in manifestations of tuberculosis, including active cavitary tuberculosis, 5 meningitis, 6 and pleurisy.…”