CN115177611A - Application of traditional Chinese medicine flavonoid compound in preparation of phosphodiesterase inhibitor - Google Patents
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Abstract
The invention discloses application of traditional Chinese medicine flavonoids in preparation of a phosphodiesterase inhibitor, wherein the traditional Chinese medicine flavonoids comprise luteolin, myricetin, apigenin, wogonin, baicalein, pecan, phaseolin, cyanidin, lycorine, chrysin, isorhamnetin, vitexin, isovitexin, ruscoside, lilac daphnetin, isorubicin, galangin, diosmetin and formononetin; the Chinese medicinal flavone has effect in inhibiting phosphodiesterase, especially PDE4 activity. Experiments prove that the traditional Chinese medicine flavonoid compound inhibits the activity of phosphodiesterase by specifically binding with the phosphodiesterase, can be used as a phosphodiesterase inhibitor, can prevent and treat inflammatory diseases induced by the phosphodiesterase, and further increases the utilization value of the traditional Chinese medicine flavonoid compound.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of traditional Chinese medicine flavonoids compounds in preparation of phosphodiesterase inhibitors.
Background
Phosphodiesterases are a member of the enzyme family, and 11 PDE enzyme families (PDE 1-PDE 11) are known to date, which differ in their substrate specificity (cAMP, cGMP or both) and their dependence on other substrates (e.g. calmodulin). Inhibition of different types of PDE isozymes leads to intracellular accumulation of cAMP and/or cGMP, which can be useful in the treatment of different inflammation-related diseases. PDE4 is mainly distributed in various inflammatory cells, such as mast cells, macrophages, eosinophils, lymphocytes and epithelial cells, and can increase intracellular concentration by inhibiting enzyme activity, which helps to reduce the harm of inflammatory reaction to the body. The major PDE isozymes are also type 4 in cells important for allergic inflammation (lymphocytes, mast cells, eosinophils, macrophages). Therefore, inhibition of PDE4 with suitable inhibitors is considered an important starting point for the treatment of various allergy-induced diseases. PDE4 inhibitors have been developed as anti-inflammatory agents, such as roflumilast, mainly for the treatment of inflammation of the lung, especially asthma and chronic obstructive pulmonary disease; difamilast is used in the treatment of atopic dermatitis; apremilast, in turn, is used in the treatment of psoriatic arthritis; meanwhile, PDE1, PDE3 and PDE5 inhibitors have also been applied to the treatment of clinical cardiovascular and cerebrovascular diseases, such as vinpocetine, dipyridamole, milrinone, sildenafil and the like. In addition, numerous documents report the use of PDE inhibitors in diseases such as chronic obstructive pulmonary disease, asthma, atopic dermatitis, rhinitis, gastritis, arthritis, psoriasis, ulcerative enteritis and acute pancreatitis, myocardial ischemia, senile dementia, parkinson's disease, cerebral ischemia, stroke, atherosclerosis, anxious depression, schizophrenia, and the like.
Although PDE4 inhibitors are known to have shown beneficial pharmacological effects, such inhibitors have adverse effects that cause diarrhea, nausea, and the like. Therefore, the research of novel specific inhibitors to overcome these adverse reactions becomes one of the hot spots of inhibitor drug research. The natural traditional Chinese medicine is a treasury for finding a lead compound for developing new medicines, and a novel inhibitor is searched from the treasury, so that the natural traditional Chinese medicine has important significance for developing an inhibitor anti-inflammatory medicine with high curative effect and small side effect.
Traditional Chinese medicine flavonoids have wide pharmacological effects, flavones are found in medicinal plants as effective components, and at present, in clinical medicines, many medicines containing flavones, especially in traditional Chinese medicine preparations, flavones play a main role as important components, for example: shuanghuanglian injection and the like. Ginkgo contains dozens of flavonoid compounds including isoflavone, flavonol, flavone, flavanone, etc., and is mainly used for treating hypertension and reducing blood lipid; however, no report about the related activity influence of traditional Chinese medicine-derived flavone compounds and PDE is found at present.
Disclosure of Invention
The invention discloses application of traditional Chinese medicine flavonoids compounds in preparation of phosphodiesterase inhibitors, and experiments prove that various traditional Chinese medicine flavonoids compounds have an obvious effect of inhibiting phosphodiesterase activity.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention provides application of traditional Chinese medicine flavonoids compounds in preparation of phosphodiesterase inhibitors.
Further, the Chinese medicinal flavonoids include luteolin, myricetin, apigenin, wogonin, baicalein, hickory nut extract, phaseolin, cyanidin, lycorine, chrysin, isorhamnetin, vitexin, isovitexin, erythrosin, genkwanin, isoerythrosin, galangin, diosmetin and formononetin.
Further, the phosphodiesterases include PDE4, PDE2, PDE3, PDE5 and PDE10.
Preferably, the phosphodiesterase is PDE4.
Furthermore, the traditional Chinese medicine flavonoid compound can be specifically combined with phosphodiesterase.
Further, the traditional Chinese medicine flavonoid compound inhibits the activity of phosphodiesterase by specifically binding with the phosphodiesterase.
The invention also provides application of the traditional Chinese medicine flavonoid compound in preparing a medicine for preventing and treating the phosphodiesterase-induced inflammatory diseases.
Further, the phosphodiesterase-induced inflammatory disease includes bronchitis, chronic obstructive pneumonia, atopic dermatitis, psoriasis, ulcerative colitis, rhinitis, gastritis, arthritis, acute pancreatitis, myocardial ischemia, senile dementia, parkinson's disease, cerebral ischemia, stroke, atherosclerosis, anxiety depression, schizophrenia.
Furthermore, the traditional Chinese medicine flavonoid compound achieves the effect of preventing and treating the inflammatory diseases induced by phosphodiesterase by inhibiting the activity of the phosphodiesterase.
Furthermore, the dosage of the traditional Chinese medicine flavonoid compound is 1-99% of the total weight of the medicine.
The medicine is in the form of tablet, oral liquid, aerosol, pill, capsule, granule, paste, drop pill, syrup, powder, granule, tincture, powder for injection or injection.
Compared with the prior art, the invention has the advantages and beneficial effects that:
experiments prove that the flavonoid compounds from traditional Chinese medicines, such as luteolin, myricetin, apigenin, wogonin, baicalein, pecan, phaseolin, cyanidin, chrysin, lycorine, isorhamnetin, vitexin, isovitexin, erythrosin, lilac daphne flower bud element, isoerythrosin, galangin, diosmetin and formononetin have remarkable effect of inhibiting phosphodiesterase activity, particularly PDE4 activity. The invention also verifies that the flavonoid compound has the effect of inhibiting the activity of PDE4 by specifically binding with PDE4, and the affinity of the lycorine and the carfolinin to the PDE4 is the best and the flavonoid compound is easy to bind, so the flavonoid compound is suitable for preparing the inhibitor of the phosphodiesterase and can relieve and prevent the diseases of inflammatory diseases induced by the phosphodiesterase by inhibiting the phosphodiesterase.
Drawings
FIG. 1 is a SPR binding map of diosmetin to PDE4.
FIG. 2 is an SPR binding map of lycorine and PDE4.
FIG. 3 is a molecular docking model of luteolin with PDE4.
FIG. 4 is a molecular docking model diagram of myricetin and PDE4.
FIG. 5 is a molecular docking model diagram of apigenin and PDE4.
FIG. 6 is a molecular docking model of wogonin and PDE4.
FIG. 7 is a molecular docking model of baicalein and PDE4.
FIG. 8 is a molecular docking model of hickory nut and PDE4.
FIG. 9 is a diagram of a molecular docking model of marrubiin with PDE4.
FIG. 10 is a diagram of a molecular docking model of cyanidin with PDE4.
FIG. 11 is a molecular docking model of eupatorin with PDE4.
FIG. 12 is a diagram of a molecular docking model of formononetin with PDE4.
FIG. 13 is a molecular docking model of galangin with PDE4.
FIG. 14 is a molecular docking model of erythrosine with PDE4.
FIG. 15 is a diagram of a molecular docking model of vitexin with PDE4.
FIG. 16 is a molecular docking model of vitexin with PDE4.
FIG. 17 is a diagram of the molecular docking model of diosmetin with PDE4.
FIG. 18 is a molecular docking model of Genkwanin and PDE4.
FIG. 19 shows the molecular docking model of chrysin and PDE4.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
The invention selects a plurality of flavonoid compounds, which are luteolin, myricetin, apigenin, wogonin, baicalein, hickory nut element, phaseolin, cyanidin, chrysin, lycorin, isorhamnetin, vitexin, isovitexin, erythroside, genkwanin, isoerythroside, galangin, diosmetin and formononetin as research objects.
Example 1: experiment for inhibiting Phosphodiesterase (PDEs) activity by various traditional Chinese medicine flavones
PDE4 activity was determined in enzyme preparations from rat polymorphonuclear lymphocytes (PMNL) and PDE2, PDE3 and PDE5 activity was determined using isolated platelet PDE. Preventing coagulation of the extracted rat blood with citrate; separating the platelet rich plasma from the red blood cells and white blood cells in the supernatant by centrifugation at room temperature; platelets were then lysed by sonication and reserved for use in the PDE3 and PDE5 assays. To determine PDE2 activity, the cytoplasmic platelet fraction was purified by NaCl gradient on an anion exchange column, obtaining the PDE2 peak for the determination; after further sedimentation by dextran, PMNL cells for PDE4 assay were isolated by Ficoll gradient centrifugation. After washing the PMNL cells 2 times, residual erythrocytes were removed by lysis for 6 minutes at 4 ℃ by adding 10mL hypotonic lysis buffer. The still intact PMNL cells were washed twice more with PBS and by sonication, centrifuged at high speed for 1h at 4 ℃ and the supernatant obtained contains the PDE4 cytoplasmic fraction for use as starting material for the enzymes in the PDE4, PDE2, PDE3 and PDE5, PDE10 assays described below.
The Activity of the above enzyme was measured using a phosphodiesterase Activity Assay kit (purchased from Abcam, inc., cat # ab13940, PDE Activity Assay kit, colorimetric): the operation method is modified appropriately, the protease provided by the kit is replaced by the protease prepared by the method, and other methods are strictly detected according to the operation instruction: adding 20 microliter of cAMP substrate, adding 15 microliter of determination buffer solution, adding 10 microliter of 5' nucleotidase, mixing uniformly, adding test compound with proper concentration, adding extracted and purified PDE enzyme, incubating at 30 ℃ for 30 minutes, adding Green Assay reagent to detect decomposed phosphate ions, mixing for 20 minutes to achieve uniform color, and determining OD620nm to calculate the inhibitory activity of the compound on the PDE enzyme.
Results the IC for PDE4 inhibition determined for each compound is shown in Table 1 s0 Value of 10 -9 -10 -5 The selectivity of M to 2, 3, 5 and 10 types of PDE is a factor of 20-1000, which shows that various traditional Chinese medicine flavonoids studied by the invention have the function of inhibiting the activity of PDE4, so that the flavonoids can be used as a specific inhibitor of PDE4.
Table 1: traditional Chinese medicine flavone for inhibiting PDIC of E4 50 Value of
| Compound (I) | IC for PDE4 inhibition 50 (μmol/L) |
| Luteolin | 10.4 |
| Myricetin | 57.8 |
| Apigenin | 51.2 |
| Wogonin | 0.31 |
| Baicalein | 72.4 |
| Carya cathayensis extract | 25.1 |
| Rock bean essence | 21.2 |
| Chrysin | 10.3 |
| Cyanidin | 17.3 |
| Herba Lycopi Linn extract | 0.22 |
| Isorhamnetin | 0.16 |
| Vitexin | 3.72 |
| Vitexin | 5.21 |
| Isovitexin | 4.26 |
| Salicornia Bigelivii Torr glycoside | 7.85 |
| Isorubiside | 10.11 |
| Galangal extract | 8.03 |
| Genkwa flower essence | 21.20 |
| Diosmetin | 0.25 |
| Miscanthus spinosa alangium essence | 16.52 |
Example 2: molecular interaction experiments
The model used in this experiment was Biacore T200, and the chip for immobilizing protein was CM5 chip. Firstly, pre-enriching the protein, diluting the protein to 1 with sodium acetate with pH 4.5, 5.0, 5.5 respectively0μg·mL -1 The optimal coupling conditions were determined by pre-enrichment experiments to be pH 6.5. Then 0.4 mol. L for chip -1 EDC and 0.1 mol. L -1 NHS is mixed and activated according to the volume ratio of 1: 1, and the protein is diluted to 10 mu g/mL by sodium acetate with the pH value of 6.0 -1 Coupling is carried out at 1 mol. L -1 Ethanolamine (pH 8.5) blocked the activated chip surface. After amino coupling of PDE4 to CM5 chips, the individual flavone monomers of the chinese herb were dissolved in DMSO to 100mM and diluted to 100. Mu.M with buffer solution PBST (1% DMSO contained) as standard injection concentration. The experimental results were analyzed by Biacore T200 Evaluation Software with data analysis Software to obtain affinity constant KD values of traditional Chinese medicine flavones and PDE4 shown in Table 2, which shows that the twenty important flavones can be specifically combined with PDE4, wherein affinity of herba Lycopodii, isovitexin and PDE4 is the best.
Table 2: affinity constant of Compounds with PDE4 on chip
| Compound (I) | KD (mol/L) obtained by SPR |
| Luteolin | 3.1*10 -7 |
| Myricetin | 1.7*10 -6 |
| Apigenin | 3.5*10 -5 |
| Wogonin | 2.1*10 -8 |
| Baicalein | 9.1*10 -6 |
| Hickory nut extract | 6.2*10 -6 |
| Rock bean essence | 8.2*10 -7 |
| Cyanidin | 3.5*10 -5 |
| Herba lycopi Linsu | 7.1*10 -9 |
| Isorhamnetin | 3.2*10 -8 |
| Vitexin | 8.2*10 -7 |
| Vitexin | 3.6*10 -8 |
| Isovitexin | 5.7*10 -9 |
| Salicornia Bigelivii Torr glycoside | 4.2*10 -6 |
| Isorubiside | 3.3*10 -8 |
| Galangal extract | 2.5*10 -7 |
| Genkwa flower essence | 5.6*10 -7 |
| Diosmetin | 6.9*10 -9 |
| Miscanthus spinosa alangium essence | 3.1*10 -6 |
Example 3: molecular docking calculations
The interaction sites of the traditional Chinese medicine flavone and PDE4 are further analyzed by adopting molecular docking software Autodock vina 1.1.2. Firstly, chemDraw Professional 15.1 software is used for drawing molecular structures of 10 traditional Chinese medicine flavones, then Chem3D 15.1 software is used for converting the molecular structures into three-dimensional structures, and MMFF94 force fields are used for energy optimization. PDE4 proteins were downloaded from a protein database (http:// www. Rcsb. Org), polar hydrogens were added using AutodockTools 1.5.6, and converted to PDBQT format. By data analysis, the active pocket coordinates of PDE4 were determined as: center _ x = -27.408, center \uy = -0.201, center \uz = -16.359; size _ x =20, size _y =38, size _z =42. To increase the accuracy of the calculation, we set the parameter exaustiveness to 20. Except as specifically noted, other parameters are default values. Finally, the conformation with the highest score value is selected and subjected to mapping and result analysis by PyMoL 1.7.6, the results are shown in figures 3-19, and the traditional Chinese medicine flavone can be combined with PDE4 protein, so that the effect of inhibiting the activity of PDE4 by combining a plurality of traditional Chinese medicine flavones researched by the invention with PDE4 is also shown, and the inflammation induced by PDE4 can be further inhibited.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (10)
1. Application of traditional Chinese medicine flavonoids compounds in preparation of phosphodiesterase inhibitors.
2. The use of a traditional Chinese medicine flavonoid compound according to claim 1 for preparing a phosphodiesterase inhibitor, characterized in that: the Chinese medicinal flavonoids include luteolin, myricetin, apigenin, wogonin, baicalein, hickory nut element, marrubiin, cyanidin, lycorine, chrysin, isorhamnetin, vitexin, isovitexin, erythroside, genkwanin, isoerythroside, galangin, diosmetin and formononetin.
3. The use of a traditional Chinese medicine flavonoid compound according to claim 1 for preparing a phosphodiesterase inhibitor, characterized in that: the phosphodiesterases include PDE4, PDE2, PDE3, PDE5 and PDE10.
4. The application of the traditional Chinese medicine flavonoid compound in preparing the phosphodiesterase inhibitor according to claim 1 is characterized in that: the traditional Chinese medicine flavonoid compound can be specifically combined with phosphodiesterase.
5. The use of a traditional Chinese medicine flavonoid compound according to claim 1 for preparing a phosphodiesterase inhibitor, characterized in that: the traditional Chinese medicine flavonoid compound inhibits the activity of phosphodiesterase by specifically binding with the phosphodiesterase.
6. Application of traditional Chinese medicine flavonoids compounds in preparation of medicines for preventing and treating phosphodiesterase-induced inflammatory diseases is provided.
7. The application of the traditional Chinese medicine flavonoid compound in preparing the medicine for preventing and treating the phosphodiesterase-induced inflammatory diseases according to claim 6, wherein the application is characterized in that: the phosphodiesterase-induced inflammatory diseases comprise bronchitis, chronic obstructive pneumonia, atopic dermatitis, psoriasis, ulcerative colitis, rhinitis, gastritis, arthritis, acute pancreatitis, myocardial ischemia, senile dementia, parkinson's disease, cerebral ischemia, stroke, atherosclerosis, anxiety depression, schizophrenia.
8. The application of the traditional Chinese medicine flavonoid compound in preparing the medicines for preventing and treating the phosphodiesterase-induced inflammatory diseases according to claim 6 is characterized in that: the traditional Chinese medicine flavonoid compound achieves the effect of preventing and treating the inflammatory diseases induced by phosphodiesterase by inhibiting the activity of the phosphodiesterase.
9. The application of the traditional Chinese medicine flavonoid compound in preparing the medicine for preventing and treating the phosphodiesterase-induced inflammatory diseases according to claim 6, wherein the application is characterized in that: the dosage of the traditional Chinese medicine flavonoid compound is 1-99% of the total weight of the medicine.
10. The application of the traditional Chinese medicine flavonoid compound in preparing the medicine for preventing and treating the phosphodiesterase-induced inflammatory diseases according to claim 6, wherein the application is characterized in that: the medicine can be tablet, oral liquid, aerosol, pill, capsule, granule, unguent, dripping pill, syrup, powder, granule, tincture, powder for injection or injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115197190A (en) * | 2021-04-09 | 2022-10-18 | 中国海洋大学 | Novel plant flavone derivative and preparation method and application thereof |
| CN115197191A (en) * | 2021-04-09 | 2022-10-18 | 中国海洋大学 | Novel traditional Chinese medicine flavone derivative and preparation method and application thereof |
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| US20090036518A1 (en) * | 2005-04-12 | 2009-02-05 | Taipei Medical University | Pharmaceutical composition containing flavonoids |
| CN107224433A (en) * | 2017-05-03 | 2017-10-03 | 广州中医药大学 | α mangostins as the inhibitor of phosphodiesterase 4 purposes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060229358A1 (en) * | 2005-04-12 | 2006-10-12 | Taipei Medical University | Pharmaceutical composition containing flavonoids |
| US20090036518A1 (en) * | 2005-04-12 | 2009-02-05 | Taipei Medical University | Pharmaceutical composition containing flavonoids |
| CN107224433A (en) * | 2017-05-03 | 2017-10-03 | 广州中医药大学 | α mangostins as the inhibitor of phosphodiesterase 4 purposes |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197190A (en) * | 2021-04-09 | 2022-10-18 | 中国海洋大学 | Novel plant flavone derivative and preparation method and application thereof |
| CN115197191A (en) * | 2021-04-09 | 2022-10-18 | 中国海洋大学 | Novel traditional Chinese medicine flavone derivative and preparation method and application thereof |
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