lxr inhibitors and uses thereof
A technology of inhibitors and uses, applied in the field of LXR inhibitors for the treatment of non-alcoholic fatty liver disease, and the field of drugs for the treatment of fatty liver disease, to achieve good treatment and remission efficacy, and to improve the effect of liver damage and steatosis.
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Embodiment 1
[0027] Example 1 Inhibition of Glabridin on LXR
[0028] Glabridin and LXR agonist (T0901317) were purchased from Shanghai Taosu Biochemical Technology Co., Ltd. pGADT7-SRC1, pGBKT7-LXR-LBD, etc. were prepared in advance in the laboratory by means of molecular cloning.
[0029] The inhibitory effect of glabridin on LXR was verified by yeast two-hybrid system. The yeast transformation method is as follows: Take a sterile 1.5ml EP tube, add in turn the pre-cooled target plasmid pGBKT7-LXR-LBD 2.5µg, pGADT7-SRC1 5µg, CarrierDNA 5µl, Y2HGold competent cells melted on ice 100µl, PEG / LiAc 500µl, gently invert and mix 6-8 times. Water bath at 30°C for 30 minutes, during which time, gently invert and mix 6-8 times every 10 minutes. Add 20 µl of DMSO to increase transformation efficiency. Afterwards, bathe in water at 42°C for 15 minutes, gently invert and mix 6-8 times every 5 minutes; centrifuge briefly at 12000rpm to discard the supernatant, resuspend with 100µl 0.9% NaCl solut...
Embodiment 2
[0037] Example 2 Molecular docking screening
[0038] Obtain the NMR structure of LXR (PDBID: 3IPQ) from the PDB database (http: / / www.rcsb.org / pdb / home / home.do), select the structure with the lowest energy and use Autodock Tools software to hydrogenate it and calculate Charge and other preprocessing. The active pocket is determined by Schroadinger software, and the Grid parameters are set to obtain 60×60×60Å 3 grid. The crystal structure was optimized using AutoDock Tools, including hydrogenation, deletion of water molecules, and completion of missing residues and side chains. After setting the Grid parameters, use autodock to perform rigid docking with the compound with optimized structure. Finally, PyMol software was used to visually analyze glabridin and its homologues, and the structure with the lowest energy was selected according to the scoring ranking and structural similarity to reduce the false positive rate, and the homologues of glabridin were initially screened ...
Embodiment 3
[0041] Embodiment 3 Animal experiments
[0042] The mice used in the experiment were healthy C57BL / 6 female mice (SPF grade) with a body weight of 20±2 g at 6-8 weeks. High-fat feed (87.8% normal feed + 10% lard + 2% cholesterol + 0.2% sodium cholate) and normal feed were provided by Shanghai Slack Experimental Animal Co., Ltd.
[0043] In order to verify the therapeutic effect of glabridin (GLA) on non-alcoholic fatty liver, 32 healthy C57BL / 6 female mice were adaptively fed for 1 week in the laboratory, and then they were divided into normal saline control group according to the random number table method. Group, model group, low-dose glabridin group (20ml / kg / d) and high-dose glabridin group (40mg / kg / d), 8 rats in each group.
[0044] The control group was fed with common feed, and the other groups were fed with high-fat feed (87.8% common feed + 10% lard + 2% cholesterol + 0.2% sodium cholate), with free intake of water and food. After 16 weeks, the feeding conditions of ...
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