Applications of 8-hydroxyquinoline drugs or salts thereof in preparation of drugs for treatment of diseases associated with BRD4
A technology of hydroxyquinoline and disease, which is applied in the field of medicine and can solve problems that have not been reported in biology or chemotherapeutic drugs
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Embodiment 1
[0044] Example 1 Virtual screening process
[0045] (1) Protein model preparation. Download the crystal structure of BRD4BD1 and inhibitor complex from Protein Data Bank, and use Pymol software to delete the non-aqueous solvent molecules in the crystal structure. Then use the "Protein Preparation Wizard" module in the Schrödinger software to complete a series of protein preparations, including hydrogenation, repairing missing residues, and energy optimization. After the protein is prepared, the non-conserved water molecules are removed. Finally, the inhibitor in the complex was selected as the "reference ligand", and the docking pocket grid file was generated using the Receptor Grid Generation program in the Glide 5.6 software.
[0046] (2) Ligand preparation. The structures of about 1,600 compounds were obtained from the database of small molecule drugs on the market, and then the three-dimensional structure, tautomer, etc. of each small molecule were generated by using th...
Embodiment 2
[0052] Compound screening and experimental verification targeting BRD4 molecular level.
[0053] By constructing a prokaryotic expression system, we successfully expressed and purified the BRD4 protein containing the BD1 domain, using the 5-, 8-, 12-, and 16-position acetylated H4 polypeptide as a substrate, and with the help of amplified chemiluminescence affinity Homogeneous detection (ALPHA) technology successfully established a screening platform targeting the BRD4BD1 domain. When no compound affects the binding of BRD4_BD1 to the substrate polypeptide, ALPHA can detect the maximum signal value, and when the small molecule inhibits the binding of BRD4_BD1 to the substrate polypeptide, the signal value will become weaker. Therefore, when the concentration of the compound gradually decreases from high to low, the signal value will gradually change from low to high, showing an S-shaped curve, which is used to fit and calculate the IC 50 value.
[0054] At the same time, we ...
Embodiment 3
[0059] Inhibition of proliferation, activation of differentiation-related target genes and induction of apoptosis by Nitroxoline in NUT-midline cancer cells.
[0060] First, using two NUT-midline cancer cell lines 797 and per433 as cell models, the IC of the compound Nitroxoline on the proliferation of the two cell lines was investigated. 50 . DMEM / F12 medium was added with 10% fetal bovine serum, cultured with double antibodies, digested with trypsin and passaged. After about 70% of cell confluence, trypsinize, make cell suspension, count cells under microscope, and then inoculate in 96-well plate, 6 plates per well, 1 cell per well. After the cells adhered to the wall, they were treated with Nitroxoline, with a concentration gradient of 100 μM as the initial concentration, and two-fold serial dilution. The change of cell proliferation after administration was detected by Alrma blue method for 72 hours. Take the cell survival rate as the ordinate and the drug concentration...
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