Design and Computational Analysis of an MMP9 Inhibitor in Hypoxia-Induced Glioblastoma Multiforme

Abstract

The main therapeutic difficulties in treating hypoxia-induced glioblastoma multiforme (GBM) are toxicity of current treatments and the resistance brought on by the microenvironment. More effective therapeutic alternatives are urgently needed to reduce tumor lethality. Hence, we screened plant-based natural product panels intending to identify novel drugs without elevating drug resistance. We explored GEO for the hypoxia GBM model and compared hypoxic genes to non-neoplastic brain cells. A total of 2429 differentially expressed genes expressed exclusively in hypoxia were identified. The functional enrichment analysis demonstrated genes associated with GBM, further PPI network was constructed, and biological pathways associated with them were explored. Seven webtools, including GEPIA2.0, TIMER2.0, TCGA-GBM, and GlioVis, were used to validate 32 hub genes discovered using Cytoscape tool in GBM patient samples. Four GBM-specific hypoxic hub genes, LYN, MMP9, PSMB9, and TIMP1, were connected to the tumor microenvironment using TIMER analysis. 11 promising hits demonstrated positive drug-likeness with nontoxic characteristics and successfully crossed blood−brain barrier and ADMET analyses. Top-ranking hits have stable intermolecular interactions with the MMP9 protein according to molecular docking, MD simulation, MM-PBSA, PCA, and DCCM analyses. Herein, we have reported flavonoids, 7,4′-dihydroxyflavan, (3R)-3-(4-hydroxybenzyl)-6-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran, and 4′-hydroxy-7methoxyflavan, to inhibit MMP9, a novel hypoxia gene signature that could serve as a promising predictor in various clinical applications, including GBM diagnosis, prognosis, and targeted therapy.

Circular RNA MMP9 interacts with HNRNPC and HRNPA1 and potentially influences the expression of BIRC5 by sequestering miR-149 and supporting glioblastoma progress

“…Glioblastoma is the most common type of cancerous brain tumor in adults and it is usually fatal because of its severe and spreading behavior (48). MMP9 had a high level of expression in various kinds of GBM such as classical, mesenchymal tissue, neural, and proneural (49). New research has revealed that the circRNA made from MMP9 boosts the formation of tumors not only in glioblastoma but also in other cancerous cells (12).…”

System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis

“…Further, the obtained list of pathways of HBV-induced hepatitis was matched with pathways collected from “KEGG ID: hsa05161” and finalized with the matched pathways for HBV-modulated pathways for further analysis. In a similar manner, the list of pathways for chemically induced hepatitis and the HBV pathways were compared for similarity based on gene counts and false discovery rate (FDR) [ 262 , 263 ].…”

Unleashing Black Sea Cucumber's Potential: Identifying Anti-Cancer Compounds Through In Silico Drug Discovery

“…The output of the docking process included *.pdbqt files containing the top ten poses and *.txt files containing the binding affinity information of the top five poses from the docking results. The results were visualized using the PyMol [83] and LigPlot programs [84].…”