CN112402402A - Application of xanthohumol in preparation of novel coronavirus inhibitor - Google Patents
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Abstract
The invention provides an application of xanthohumol in preparation of a novel coronavirus inhibitor. The invention takes Mpro protease of novel coronavirus causing lung inflammation as a target spot, and obtains an antiviral active compound-xanthohumol with strong binding capacity with the Mpro protease through virtual screening based on a structure. The xanthohumol inhibits the activity of Mpro protease by combining with the target Mpro protease, thereby inhibiting the replication and transcription of viruses and achieving the effect of resisting the infection of the novel coronavirus. The xanthohumol can be applied to the preparation of a novel coronavirus Mpro protease inhibitor, so that the xanthohumol can be applied to the preparation of a medicament for preventing and/or treating novel coronavirus inflammation. The binding energy of the xanthohumol of the invention to the Mpro protease is: 63.427KJ/mol, IC for Mpro protease504.97 +/-1.79 mu M, inhibitThe constant Ki was set to 2.14. mu.M.
Description
Technical Field
The invention relates to the technical field of xanthohumol application, in particular to application of xanthohumol in preparation of a novel coronavirus inhibitor.
Background
The novel coronavirus (SARS-CoV-2) is a new strain of coronavirus found in human in 2019, and pneumonia caused by its infection is called novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19). The novel coronavirus pneumonia is mainly transmitted and contacted through respiratory droplets, is generally susceptible to crowds and has high infectivity. The novel coronavirus pneumonia rapidly rolls around the world after 12 months outbreak in 2019. Currently, the world health organization has classified new coronavirus pneumonia as a global pandemic, which is also the first global pandemic caused by coronaviruses. By 10, 28 days in 2020, more than 4400 ten thousand patients have been diagnosed with the novel coronavirus pneumonia globally, and the cumulative number of deaths exceeds 110 ten thousand.
The novel coronavirus pneumonia is mainly characterized by fever, dry cough and hypodynamia, about 50 percent of patients have dyspnea after 1 week, and severe patients can quickly progress to symptoms such as acute respiratory distress syndrome, septic shock, metabolic acidosis which is difficult to correct, blood coagulation dysfunction and the like. Despite the good prognosis in most patients, a proportion of patients develop acute respiratory distress syndrome or septic shock and even die. The novel coronavirus pneumonia has no specific treatment medicine at present, and various oxygen treatment, symptomatic treatment and immunoregulation treatment are adopted clinically. However, some severe patients still have no obvious curative effect after antiviral treatment and anti-inflammatory treatment, and are easy to be infected together, so that multiple and diffuse lesions are caused. The current medicines and treatment methods can not meet the clinical requirements, and the research and development of novel treatment medicines for treating coronavirus inflammation have great social and economic significance.
Disclosure of Invention
The invention aims to provide application of xanthohumol in preparation of a novel coronavirus inhibitor, and aims to solve the problem that medicines and treatment methods for treating novel coronavirus inflammation in the prior art cannot meet clinical needs.
In order to solve the technical problem, the technical scheme of the invention is realized as follows:
in one aspect, the present invention provides the use of xanthohumol in the preparation of a novel coronavirus Mpro protease inhibitor.
The genome of the novel coronavirus (SARS-CoV-2) contains about 30000 nucleotides, and the replicase of SARS-CoV-2 encodes two high homology polyproteins pp1a and pp1ab, pp1a and pp1ab, which are essential for viral replication and transcription. The main protease (Mpro, 3CLpro, nsp5) of the novel coronavirus (SARS-CoV-2) is a cysteine protease that releases functional polypeptides by hydrolytic digestion. The main protease Mpro, starting from the autolytic cleavage of pp1a and pp1ab, will hydrolytically digest the polyprotein from at least 11 conserved sites to form a functional polypeptide. The Mpro protease plays a key role in the life cycle of viral replication and transcription, and lacks homologous genes closely related to humans; therefore, the Mpro protease is a potential antiviral drug design target. The invention utilizes the xanthohumol to prepare the target novel coronavirus Mpro protease target inhibitor, the xanthohumol and the inflammatory target Mpro protease such as lung caused by the novel coronavirus have stronger bonding strength, and the activity of the Mpro protease can be inhibited, so that the transcription and the replication of the virus are inhibited, and the inhibitor has potential treatment effect on pneumonia caused by the novel coronavirus.
In another aspect, the present invention provides the use of xanthohumol in the preparation of a novel coronavirus inhibitor.
The Xanthohumol of the invention contains Xanthohumol in preparing a novel coronavirus inhibitor, wherein the Xanthohumol (Xanthohumol) is a member of chalcone compounds, and is trans-chalcone which is substituted by hydroxyl at the 4,2 'and 4' positions, has methoxyl at the 6 'position and has pentenyl at the 3' position. Xanthohumol is separated from flos Lupuli, is inhibitor of DGAT, COX-1 and COX-2, has antitumor and antiangiogenic effects, and also has antiviral activity against BVDV, HSV-1, HSV-2 and CMV. The structural formula of the xanthohumol is shown as the formula (I):
the xanthohumol and the Mpro protease which is an inflammation target spot such as lung and the like caused by the novel coronavirus have stronger bonding strength and can inhibit the activity of the Mpro protease, thereby preparing the novel coronavirus inhibitor.
In a further aspect, the invention provides the use of xanthohumol in the manufacture of a medicament for the prevention and/or treatment of novel coronavirus inflammation.
The medicine for preventing and/or treating the novel coronavirus inflammation contains xanthohumol, and the xanthohumol and the Mpro protease which is an inflammation target spot such as lung caused by the novel coronavirus have stronger bonding strength and can inhibit the activity of the Mpro protease, so that the medicine for preventing and/or treating the novel coronavirus inflammation is prepared.
Further, the medicine is any one of capsules, tablets, pills, granules, electuary, injection or spray. The dosage form of the medicine for preventing and/or treating the novel coronavirus inflammation can be various, such as capsules, tablets, pills, granules, injection agents or sprays, namely, the xanthohumol is prepared into the medicine for preventing and/or treating the novel coronavirus inflammation by matching with various auxiliary materials, so that different requirements are met.
Compared with the prior art, the invention has the beneficial effects that: the xanthohumol and the Mpro protease which is an inflammation target spot such as lung and the like caused by the novel coronavirus have stronger bonding strength, and can inhibit the activity of the Mpro protease so as to inhibit the transcription and the replication of the virus, so that the xanthohumol can be used for preparing a targeted novel inhibitor of the Mpro protease target spot of the coronavirus, the xanthohumol can also be used for preparing a novel coronavirus inhibitor, and the xanthohumol is used for preparing a medicine for preventing and/or treating the inflammation of the novel coronavirus, and the medicine has a potential treatment effect on the pneumonia caused by the novel coronavirus.
Drawings
FIG. 1 is a diagram showing the binding pattern of xanthohumol to the Mpro protease as a target of a novel coronavirus in the present invention;
FIG. 2 is a graph showing the mean free energy of binding of xanthohumol and Mpro protease;
FIG. 3 is a graph showing the inhibition of Mpro protease activity by xanthohumol at different concentrations;
FIG. 4 is a line graph of the inhibition of Mpro protease activity by xanthohumol;
FIG. 5 is a graph showing the inhibition of the activity of Mpro protease by chloroquine phosphate at different concentrations.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1 binding Pattern of xanthohumol to Mpro, a novel coronavirus Main protease
(1) Experimental Material
In this example, the three-dimensional structure (PDB ID:6LU7) of SARS-CoV-2 virus primary protease Mpro, which was analyzed by Shanghai university of science and technology team in protein database (RCSB PDB), was used as a receptor; adopting software such as AutoDock Vina, Gromacs 2019 and g _ MMPBSA for calculation; carrying out visual analysis on PyMol, Grace and R; the drugs on the market in Qingdao Marine biological medicine research institute and the drugs in clinical research drug library are adopted for virtual screening.
(2) Experimental methods
Based on a super computer of a national laboratory high-performance scientific calculation and system simulation platform for Qingdao ocean science and technology trial, taking marketed drugs in Qingdao ocean biomedical research institute and drugs in a clinical research drug library as screening objects, firstly, performing molecular docking on drug molecules and Mpro protease by adopting AutoDock Vina, and calculating the distance between atoms to obtain the interaction between the drug molecules and the Mpro protease; performing primary screening according to the interaction (hydrogen bond) of the drug molecules and the Mpro protease and the consistency evaluation of docking score (< -6kcal/mol), and screening out xanthohumol; secondly, performing 10ns molecular dynamics simulation by adopting a Gromacs program, taking a root mean square error RMSD value (<0.2) of the sampling structure according to a simulation result, and intercepting a balanced 2ns structure; finally, the mean binding energy (i.e., mean free energy of binding) of xanthohumol on the structure 2ns after equilibration was calculated using the MM-PBSA method using the g _ MMPBSA program.
(3) Results of the experiment
The calculation results show that: xanthohumol has a high affinity for Mpro protease, an average binding energy predicted by molecular docking of-7.0 kcal/mol, and is capable of binding to the substrate binding site of Mpro protease. Referring to FIG. 1, the hydroxyl group of the p-hydroxyphenylketene moiety of xanthohumol forms a pair of hydrogen bonds with threonine at position 190 of Mpro protease (THR-190), and the hydroxyl group at position C4 of the 6-methoxy-3- (3-methyl-2-butene) -resorcinol moiety of xanthohumol forms a pair of hydrogen bonds with each of glycine at position 143 of Mpro protease (GLY-143), serine at position 144 of Mpro protease (SER-144), and cysteine at position 145 of Mpro protease (CYS-45). Among them, cysteine at position 145 is a key residue for the catalytic activity of Mpro protease, and it is well established that the interaction of xanthohumol with Mpro protease directly affects its activity.
With reference to FIG. 2, calculated using the MM-PBSA method: the mean free energy of binding of xanthohumol to the Mpro protease is: 63.427KJ/mol, which shows that xanthohumol has strong binding energy with Mpro protease of novel coronavirus target, thereby inhibiting Mpro protease activity and influencing transcription and replication of virus. Therefore, xanthohumol has potential therapeutic effect on pneumonia caused by the novel coronavirus.
Example 2 assay of the inhibitory Activity of xanthohumol on the Mpro protease of a novel coronavirus target
(1) Experimental Material
The recombinant plasmid containing the Mpro protease gene was synthesized by Wuhan Projian Bio Inc; ni Beads were purchased from SmartLifeScience; multifunctional microplate reader SpectraMax i3 was purchased from Molecular Device, usa; 96-well blackboards were purchased from Corning, usa; xanthohumol and other commonly used reagents were purchased from Sigma.
(2) Experimental methods
a. Expression and purification of recombinant Mpro protease
The Mpro protease recombinant plasmid (pET28a (+)) containing SARS-CoV-2 origin was transformed into E.coli strain BL21 (condiplus), and the strain was grown to OD in LB medium6000.6-0.8, then, 0.4mM isopropyl-1-thio-beta-D-galactoside (IPTG) is added to continue growth at 16 ℃ for 12 hours for low temperature induced expression. According to the volume ratio of 1: 5, adding a lysate into the suspension, resuspending the bacterial solution, crushing the thalli by ultrasonic and high-pressure crushing and the like, centrifuging, taking the supernatant, performing affinity chromatography purification by Ni Beads according to the instructions of a manufacturer, verifying the protein purity by adopting an SDS-PAGE method to obtain the purified Mpro protease, and storing the purified Mpro protease in a refrigerator.
b. Assay for Mpro protease inhibitory Activity of xanthohumol
To a test tube containing 1mg of the substrate, 230. mu.L of dimethyl sulfoxide (DMSO) was added to give a final substrate concentration of 1 mM; shaking at room temperature in dark for 10 min, subpackaging 20 μ L per tube, and freezing the rest at-20 deg.C. The purified Mpro protease of step a was removed from the freezer and placed at room temperature for 5 minutes to thaw and begin the activity test.
The IC50 test method is as follows: first, 48. mu.L of reaction buffer (50mM Tris-HCl (pH 7.3), 1mM EDTA) and 1. mu.L of purified Mpro protease were added to each well to prepare a mixture, and the final concentration of the purified Mpro protease in the mixture was 100 nM; secondly, adding 1 mu L of xanthohumol with different concentrations, wherein the concentrations of the xanthohumol are respectively 0, 0.63, 1.25, 2.5, 5, 7.5, 10, 12.5 and 25 mu M, fully mixing the components, and standing the mixture for 30 minutes at room temperature; next, 49. mu.L of the reaction buffer and 1. mu.L of the substrate group were addedThe final concentration of the substrate in the mixed solution is 2 mu M; finally, measuring by using a multifunctional microplate reader, wherein the excitation wavelength is 320nm, the emission wavelength is 405nm, reading is carried out for 1 time every 30 seconds, continuously recording for 15 minutes, and taking the slope in the linear interval as V0And calculating the IC of xanthohumol for the Mpro protease50。
The Ki test method comprises the following steps: first, 48. mu.L of reaction buffer (50mM Tris-HCl (pH 7.3), 1mM EDTA) and 1. mu.L of purified Mpro protease were added to each well to prepare a mixture, and the final concentration of the purified Mpro protease in the mixture was 100 nM; secondly, adding 1 mu L of xanthohumol with different concentrations, wherein the concentrations of the xanthohumol are respectively 0, 0.63, 1.25, 2.5, 5, 7.5, 10, 12.5 and 25 mu M, fully mixing the components, and standing the mixture for 30 minutes at room temperature; next, 49. mu.L of a mixture of the reaction buffer and 1. mu.L of the substrate (final concentration: 2. mu.M) and 49. mu.L of a mixture of the reaction buffer and 1. mu.L of the substrate (final concentration: 4. mu.M) were added, respectively, using a multi-channel pipette; finally, the initial rates of enzymatic hydrolysis of substrates with different concentrations in the presence of xanthohumol are determined, and Km and V before and after xanthohumol addition are determined according to a Lineweaver-Burk mapping methodmaxThe inhibition constant Ki can be determined by the ratio of the slopes of the two lines.
(3) Results of the experiment
Results of experiments for testing Mpro protease inhibitory activity of xanthohumol, see FIG. 3, the IC of xanthohumol for Mpro protease50Comprises the following steps: 4.97 +/-1.79 mu M; referring to FIG. 4, the inhibition constants Ki values for xanthohumol for Mpro protease are: 2.14. mu.M.
The conclusion from the above experimental results is: the xanthohumol has strong combination with the main protease Mpro of the novel coronavirus, and has the function of inhibiting the protease activity of the Mpro of the coronavirus, so the xanthohumol has the function of preventing and treating pneumonia caused by the novel coronavirus, and can be applied to the preparation of anti-pneumonia medicaments.
Comparative example 1 chloroquine test for inhibitory Activity on Mpro protease, a novel coronavirus target
Chloroquine Phosphate (Chloroquine Phosphate) is used as a candidate drug in developing clinical experiments of new coronavirus, and a certain treatment effect is initially shown. The inhibitory activity of chloroquine phosphate against the Mpro protease was tested under the same experimental conditions as for xanthohumol.
Referring to FIG. 5, the IC50 for chloroquine phosphate on Mpro protease is: 11.95. + -. 0.54. mu.M. Therefore, compared with chloroquine phosphate, the xanthohumol has higher inhibitory activity with the main protease Mpro of the novel coronavirus and has stronger effect on preventing and treating pneumonia caused by the novel coronavirus.
Therefore, the invention firstly predicts the binding mode of the xanthohumol and the Mpro target of the novel coronavirus main protease by using methods such as molecular docking, molecular simulation and the like, and then calculates the binding free energy of the xanthohumol and the Mpro protease by using g _ MMPBSA. The inhibition effect of the xanthohumol on the Mpro protease is verified through an enzyme activity test experiment, and the IC50 and Ki values of the xanthohumol on the Mpro protease are obtained through the activity test experiment; this indicates that xanthohumol can bind to the substrate binding site of the Mpro protease target of the novel coronavirus to inhibit the activity of the Mpro protease, thereby inhibiting the replication and transcription of the virus; therefore, the xanthohumol has the effect of preventing and/or treating the novel coronavirus inflammation, and can be applied to the preparation of medicaments for preventing and/or treating the novel coronavirus inflammation.
The invention takes Mpro protease of novel coronavirus causing lung inflammation as target spot, and obtains an antiviral active compound-xanthohumol with strong binding ability with the Mpro protease through virtual screening based on structure. The xanthohumol inhibits the activity of Mpro protease by combining with the target Mpro protease, thereby inhibiting the replication and transcription of viruses and achieving the effect of resisting the infection of the novel coronavirus. The xanthohumol can be applied to the preparation of a novel coronavirus Mpro protease inhibitor, and can also be applied to the preparation of a novel coronavirus inhibitor, so that the xanthohumol can be applied to the preparation of a medicine for preventing and/or treating novel coronavirus inflammation. The mean free energy of binding of xanthohumol of the invention to Mpro protease is-63.427 KJ/mol, IC of xanthohumol to Mpro protease504.97. + -. 1.79. mu.M, and the inhibition constant Ki value of xanthohumol for the Mpro protease is 2.14. mu.M.
Therefore, compared with the prior art, the invention has the beneficial effects that: the xanthohumol and the Mpro protease which is an inflammation target spot such as lung and the like caused by the novel coronavirus have stronger bonding strength, and can inhibit the activity of the Mpro protease so as to inhibit the transcription and the replication of the virus, so that the xanthohumol can be used for preparing a targeted novel inhibitor of the Mpro protease target spot of the coronavirus, the xanthohumol can also be used for preparing a novel coronavirus inhibitor, and the xanthohumol is used for preparing a medicine for preventing and/or treating the inflammation of the novel coronavirus, and the medicine has a potential treatment effect on the pneumonia caused by the novel coronavirus.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. Application of xanthohumol in preparing novel coronavirus Mpro protease inhibitor is provided.
2. Use of xanthohumol in the preparation of novel coronavirus inhibitors.
3. Application of xanthohumol in preparing medicine for preventing and/or treating coronavirus inflammation is disclosed.
4. Use of xanthohumol according to claim 3 in the preparation of a medicament for the prevention and/or treatment of novel coronavirus inflammation characterized in that: the medicine is any one of capsules, tablets, pills, granules, electuary, injection or spray.
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Cited By (2)
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| CN115737675A (en) * | 2022-11-28 | 2023-03-07 | 安徽农业大学 | Preparation of oxidized sodium selenosulfate and application of oxidized sodium selenosulfate in treatment of coronavirus infection |
| EP4162932A1 (en) * | 2021-10-07 | 2023-04-12 | HHV Hallertauer Hopfenveredelungsgesellschaft mbH | Antiviral hop constituents |
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Cited By (3)
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| EP4162932A1 (en) * | 2021-10-07 | 2023-04-12 | HHV Hallertauer Hopfenveredelungsgesellschaft mbH | Antiviral hop constituents |
| CN115737675A (en) * | 2022-11-28 | 2023-03-07 | 安徽农业大学 | Preparation of oxidized sodium selenosulfate and application of oxidized sodium selenosulfate in treatment of coronavirus infection |
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Application publication date: 20210226 |