CN112315955A - S100A8/A9 protein inhibitor gambogic acid and application thereof - Google Patents
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Abstract
The invention relates to a new application of gambogic acid as an S100A8/A9 protein inhibitor and application thereof, and discloses a new application of a new old medicine, which is characterized in that an FDA approved medicine is subjected to computer virtual screening of a molecular docking model based on a crystal structure of S100A8/A9, and a molecular docking simulation process is carried out, so that the gambogic acid can be stably bound to a CHAPS binding site of an S100A9 dimer, and the formation and the stability of an S100A8/A9 heterotetramer are influenced by inhibiting S100A9 dimerization and simultaneously inhibiting S100A9 dimerization in an S100A8/A9 heterotetramer, and the invention not only provides a new application for the gambogic acid, but also provides an example for the rapid development of a novel S100A8/A9 protein inhibitor.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a novel application of gambogic acid as an S100A8/A9 protein inhibitor and an application thereof.
Background
The S100 protein comprises 25 known members and is an important family of multifunctional calcium binding proteins. The S100A8 and S100a9 proteins are major members of the S100 protein family, and can form heterodimers, heterotetramers, etc. in vitro and in vivo, and exist as oligomers (S100A8/a9, also known as Calprotectin), thereby playing an important role in the regulation of inflammation and immune response. At the site of infection or sterile injury, granulocytes and monocytes highly express the S100A8/A9 protein and secrete outside the cell. The S100A8/A9 protein acts as a risk associated molecular patterns (DAMPs) protein and an alarm (alarmin), interacts with a pattern recognition receptor Toll-like receptor 4(TLR4) and a advanced glycation end product (RAGE), activates intracellular NF-kB and MAPK pathways, aggregates inflammatory cells through chemotaxis on neutrophils, and secretes inflammatory cytokines and chemokines, thereby exerting a pro-inflammatory effect.
The serum concentration of S100A8/A9 is proved to reflect the severity of various inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and psoriasis, the stability and the sensitivity of the serum concentration are superior to those of C-reactive protein (CRP), and the S100A8/A9 protein is considered to be a better inflammation-related biomarker.
In addition, other studies show that the S100A8/A9 inhibitor can achieve the purpose of anti-inflammation through interaction with the inhibitor, and has good effect in the treatment of systemic lupus erythematosus; S100A8/A9 is also involved in the pathophysiological processes of other diseases, including: S100A8/A9 induces BV-2 microglia to be activated by activating an NF-kB signal channel, promotes the generation of proinflammatory factors and further aggravates OPC injury; blocking the combination of the S100A8/A9 protein and a receptor thereof can inhibit the migration of neutrophils after myocardial infarction and improve the cardiac function; inhibition of S100A8/A9 can prevent the induction of proinflammatory cytokines and the activation of NF-kB after hypoxia, and delay the progress of heart failure; the S100A8/A9 mediates the accumulation of neutrophils in the development process of chronic tuberculosis, and the S100A8/A9 protein inhibitor controls the inflammation caused by mycobacterium tuberculosis (Mtb) of patients with non-acute tuberculosis; song G et al developed a new monoclonal antibody against S100A8/A9, which could effectively prevent the metastasis of lung cancer; in addition, research shows that Melanoma Cell Adhesion Molecules (MCAM) are important receptors of S100A8/A9, the combination of S100A8/A9 and MCAM leads to the metastasis of melanoma cells to lung tissues, and the combination of S100A8/A9 and cell surface receptor Melanoma Cell Adhesion Molecules (MCAM) accelerates the growth and metastasis of breast cancer and prostate cancer; S100A8/A9 mediates kidney injury and fibrosis, possibly through interaction with tubular epithelial cells resulting in irreversible injury, and inhibition of S100A8/A9 is a therapeutic strategy for preventing renal fibrosis in patients with chronic kidney disease. The above suggests that S100A8/A9 is a promising drug target. In view of the above, the project is designed to screen and develop small molecule compounds with S100A8/A9 as target proteins.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel small molecule compound which is combined with the S100A8/A9 protein in a targeted way.
The invention provides application of gambogic acid in preparing a S100A8/A9 protein targeted inhibition binding agent.
Further, the binding target of gambogic acid is located in the hydrophobic amino acid or the hydrophobic side chain part of the hydrophilic amino acid of the S100A9 protein in the S100A8/A9 protein.
Further, the binding target of gambogic acid comprises Arg85, Leu86, Leu49, Glu52, Glu64, His61 of one S100A9 protein in the S100A8/A9 protein and His61, Lys57, Lys54 and Glu52 amino acid sites of the other S100A9 protein.
Further, gambogic acid is used for preparing the S100A8/A9 protein targeted inhibition binding agent as an anti-inflammatory drug; or an anti-cancer drug; or a myocardial infarction prognostic drug; or a drug for relieving heart failure; or drugs for ameliorating chronic pulmonary tuberculosis; or a medicament for treating chronic kidney disease and renal fibrosis.
Further, gambogic acid is used as an anti-inflammatory drug in preparation of the targeted inhibition binding agent of the S100A8/A9 protein, and inflammation comprises uveitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and psoriasis.
Further, the S100A8/A9 protein targeted inhibition binding agent is used as an anti-cancer drug, and cancers comprise lung cancer, breast cancer, prostate cancer and melanoma.
The invention has the following advantages: based on the new use of old drugs, the invention carries out computer virtual screening of a molecular docking model on FDA approved drugs through a crystal structure based on S100A8/A9, and a molecular docking simulation process finds that gambogic acid can be stably bound on a CHAPS binding site of an S100A9 dimer, inhibits S100A9 dimerization in an S100A8/A9 heterotetramer while inhibiting S100A9 dimerization, or inhibits S100A9 dimerization in other S100A8/A9 oligomers, thereby influencing the formation and stability of an S100A8/A9 protein, and in vitro and in vivo experiments also show that the gambogic acid is an inhibitor of the S100A9 dimer and the S100A8/A9 protein, thereby proving that the gambogic acid is a new use of the S100A9 dimer and the S100A8/A9 protein inhibitor. The invention not only provides a new application for gambogic acid, but also provides an example for the rapid development of a novel S100A8/A9 protein inhibitor.
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FIG. 1 gambogic acid interactive chemical model;
FIG. 2(a) the tetrameric structure S100A8/A9, with the A/B chain being S100A8 and the C/D chain being S100A 9; (b) the binding site of S100a9 (at a); (c) crystal structure of S100a9 dimer, S100a9 dimer inhibitor CHAPS, steric hindrance (at B);
FIG. 3 is a molecular docking scheme for gambogic acid;
FIG. 4(a) graph of interaction of gambogic acid and S100A9 protein; (b) specific experimental data for the interaction curve;
figure 5(a) the concentration of inflammatory cytokine IL-6 in cell supernatants was measured by ELISA kit and the data were mean ± SD, P < 0.05 compared to LPS group; (b) measuring the concentration of inflammatory cytokine TNF- α in the cell supernatants by ELISA kit, data as mean ± SD, P < 0.0005 compared to LPS group; FIG. 6(a) anterior ocular segment inflammation was not observed in the normal control group; (b) pupillary constriction, vasodilation, and even flexion into a spiral (arrow), anterior chamber exudate (thick arrow) were observed in LPS group under slit lamp 24 hours after LPS injection; (c) only slight vasodilation (arrow) was observed in 2752-65-0(10 μ M) + LPS group; (d) clinical scores of different groups after LPS injection, P < 0.0001 compared to LPS group. Figure 7 effect of gambogic acid on infiltration cell and protein concentration in aqueous humor, P < 0.0001 compared to LPS group.
Detailed Description
The present invention will be further described in detail with reference to the following examples and effect examples, which are not intended to limit the scope of the present invention, but are not intended to limit the scope of the present invention. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Gambogic acid is an amorphous/crystalline orange solid with molecular formula of C38H44O8The molecular weight is 628.7g/mol, the boiling point is 808.9 ℃, the melting point is 251.4 ℃, and the maximum absorption wavelength is 365 nm.
Example 1: garcinia acid and S100A9 dimer molecule docking virtual model
The crystal structure (ID: 1XK4) of S100A8/A9 is shown in FIG. 2a, the A chain and B chain are S100A8, and the C chain and D chain are S100A 9. Because it forms a stable tetrameric configuration, it is difficult to optimize reasonable binding sites by molecular dynamics simulations. Further analysis shows that the crystal structure (ID: 1IRJ) of S100A9 has a binding site of a small molecule CHAPS, which can inhibit the activity of S100A9 and provide the possibility of virtual screening.
By analysis of the S100a9 dimerization crystal structure, the binding site of CHAPS (S100a9 dimerization inhibitor) corresponds to the binding sites of two S100a9 in the S100A8/a9 tetramer (fig. 2b indicates at arrow a). The S100A9 dimer crystal structure (PDB ID: 1IRJ) was congruent with the S100A8/A9 heterotetramer crystal structure (PDB ID: 1XK4), and from FIG. 2C it can be seen that the S100A9 dimerization inhibitor, CHAPS, can inhibit S100A9 dimerization in the S100A8/A9 tetramer (steric hindrance with the C-terminal Trp88, His91, Glu92 of S100A9, arrow B). Therefore, the inhibitor for S100A9 dimerization can inhibit S100A9 dimerization independently, and also can obviously inhibit S100A9 dimerization in S100A8/A9 heterotetramers, thereby influencing the formation and stability of S100A8/A9 heterotetramers. In view of this, we determined that the CHAPS binding site of the S100A9 dimer was used as a virtual screening binding site, and the crystal structure adopted was 1 IRJ.
Through screening the compounds from different data, the binding effect of gambogic acid to the CHAPS binding site of the S100A9 dimer is good, and the molecular docking mode of gambogic acid is shown in FIG. 3. In the figure, the symbol a indicates a gambogic acid compound. Two identical S100a9 have some critical amino acid residues on the interacting surface, and it is these amino acids that are involved in binding to small molecule compounds. Gambogic acid is integrated in hydrophobic oral cavity formed by a large number of hydrophobic amino acids (or hydrophobic side chain portions of hydrophilic amino acids) such as Arg85, Leu86, Leu49, Glu52, Glu64, His61 on S100a9 and His61, Lys57, Lys54, Glu52 on the other S100a 9.
Example 2: interaction of gambogic acid and S100A9 dimer molecule
Biomolecular interactions were detected and analyzed using an Octet platform based on biofilm interference technology (BLI). The experimental Data was processed through Data Analysis software 9.0. Selecting a fitting model: 1: 1 model, i.e. 1 fitting mode of S100A8/A9 protein binding to 1 small molecule gambogic acid: global, i.e. grouping 6 concentrationsAnd (6) analyzing the association. Preparing 25, 12.5, 6.25, 3.13, 1.56 μ M gambogic acid solution, detecting gambogic acid with concentration different from 100 μ L6 group and CaCl with concentration of 100 μ L200 μ M after solidifying S100A8/A9 protein on chip2Signals and data interacting with 100 μ L of 5% DMSO + PBST buffer; detecting blank chip, gambogic acid of different concentrations, and CaCl of 100 μ L concentration of 200 μ M2Signals and Data from the interaction with 100 μ L of 5% DMSO + PBST buffer were processed through Data Analysis software 9.0.
Through the analysis, the interaction between the small molecule drug and the S100A8/9 protein is verified, and the result is shown in FIG. 4, the binding signal between the S100A8/A9 protein and gambogic acid increases along with the increase of the concentration of the gambogic acid, the binding signal and the gambogic acid are in positive correlation, and the interaction between the S100A8/A9 protein and the gambogic acid is verified.
Example 3: garcinolic acid in vitro cell anti-inflammatory effect
Preparing an LPS-stimulated Raw264.7 cell inflammation model, selecting 0.2 mu M gambogic acid of drug concentration to be added into a culture medium, setting a normal Raw264.7 cell group and a Raw264.7 cell inflammation model control group which is not added with the LPS stimulation of the gambogic acid, and measuring the concentration of inflammatory cytokines in cell supernatant through an ELISA kit after 24 hours, wherein the result is shown in figure 5, the LPS stimulation promotes the obvious up-regulation of IL-6 and TNF-alpha in the cell supernatant, and the gambogic acid can inhibit the secretion of the IL-6 and the TNF-alpha and shows better in-vitro anti-inflammatory effect.
Example 4: anti-inflammatory effect of gambogic acid on pre-treatment uveitis
An LPS-induced anterior uveitis rat model (EIU) was prepared by injecting LPS into Waistar rat hindfoot pads, and 100. mu.l of LPS was injected into each foot pad at a rate of 1mg/ml, and the EIU model was prepared by injecting 100. mu.l of sterile saline into Waistar rat hindfoot pads as a normal control group, diluting the test group with 10mM gambogic acid at 100. mu.M with sterile saline, injecting 2. mu.l of gambogic acid into the vitreous humor of both eyes of the LPS-induced anterior uveitis rat model, and observing the inflammation conditions of the normal control group, LPS group and test group 24 hours later, respectively, and evaluating the clinical scores of inflammatory responses of the normal control group, LPS group and test group.
And the number of permeated cells in the aqueous humor was measured to confirm the anti-inflammatory effect of gambogic acid in EIU. 24 hours after LPS injection, the number of aqueous humor cells in LPS group was significantly increased, but almost no cells were found in normal group. The number of infiltrating inflammatory cells in the aqueous humor of the gambogic acid (100. mu.M) administered group was significantly reduced compared to the LPS group, and the results are shown in FIG. 7.
Finally, it must be said here that: the above embodiments are only used for further detailed description of the technical solutions of the present invention, and should not be understood as limiting the scope of the present invention, and the insubstantial modifications and adaptations made by those skilled in the art according to the above descriptions of the present invention are within the scope of the present invention.
Claims (6)
1. Use of gambogic acid in the preparation of S100A8/a9 protein targeted inhibition binding agents.
2. The use of gambogic acid in the preparation of a targeted inhibition binding agent to S100A8/a9 protein according to claim 1, wherein the binding target of gambogic acid is located at the hydrophobic amino acid or the hydrophobic side chain portion of the hydrophilic amino acid of S100a9 protein in the S100A8/a9 protein.
3. Use of gambogic acid according to claim 1 or 2 in the preparation of a targeted inhibitory binding agent to S100A8/a9 protein, wherein the binding target of gambogic acid comprises Arg85, Leu86, Leu49, Glu52, Glu64, His61 of one of the S100a9 proteins and the His61, Lys57, Lys54, Glu52 amino acid sites on the other S100a9 protein.
4. Use of gambogic acid in the preparation of a S100A8/a9 protein targeted inhibition binding agent according to claim 1, wherein the S100A8/a9 protein targeted inhibition binding agent is used as an anti-inflammatory drug; or an anti-cancer drug; or a myocardial infarction prognostic drug; or a drug for relieving heart failure; or drugs for ameliorating chronic pulmonary tuberculosis; or a medicament for treating chronic kidney disease and renal fibrosis.
5. Use of gambogic acid according to claim 4 in the preparation of targeted inhibitory binding agents to the S100A8/a9 protein, wherein the targeted inhibitory binding agent to the S100A8/a9 protein is used as an anti-inflammatory agent and the inflammation comprises uveitis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis.
6. The use of gambogic acid in the preparation of S100A8/a9 protein targeted inhibition binding agent according to claim 4, wherein the S100A8/a9 protein targeted inhibition binding agent is used as an anticancer drug, and the cancer comprises lung cancer, breast cancer, prostate cancer and melanoma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113855666A (en) * | 2021-11-18 | 2021-12-31 | 华中科技大学同济医学院附属同济医院 | Application of gambogic acid in preparation of medicine for preventing or treating renal ischemia-reperfusion injury |
| CN114569601A (en) * | 2022-04-21 | 2022-06-03 | 四川大学华西医院 | Application of neogambogic acid in preparation of medicine for preventing and/or treating kidney diseases |
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Cited By (2)
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| CN113855666A (en) * | 2021-11-18 | 2021-12-31 | 华中科技大学同济医学院附属同济医院 | Application of gambogic acid in preparation of medicine for preventing or treating renal ischemia-reperfusion injury |
| CN114569601A (en) * | 2022-04-21 | 2022-06-03 | 四川大学华西医院 | Application of neogambogic acid in preparation of medicine for preventing and/or treating kidney diseases |
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Application publication date: 20210205 |