CN113813271B - Application of forsythoside F in preparation of anti-coronavirus product - Google Patents
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- DTOUWTJYUCZJQD-UJERWXFOSA-N Forsythiaside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](OC(=O)\C=C\C=2C=C(O)C(O)=CC=2)[C@H](O)[C@@H](O)[C@H](OCCC=2C=C(O)C(O)=CC=2)O1 DTOUWTJYUCZJQD-UJERWXFOSA-N 0.000 abstract 1
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- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Engineering & Computer Science (AREA)
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- Otolaryngology (AREA)
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Abstract
The invention discloses application of forsythoside A F in preparation of an anti-coronavirus product, and belongs to application in the field of medicines. The molecular docking technology is adopted to prove the inhibition effect of the forsythoside F on the S protein and ACE2 protein of the novel coronavirus COVID-19, and the affinity experiment determines that the forsythoside F has stronger affinity with the S protein. The antiviral experiment shows that the forsythoside F has remarkable inhibition effect on coronavirus within the range of 1 mu M to 100 mu M, and the effect and the dosage are in dose-effect relationship. Forsythoside F is a specific inhibitor of coronaviruses, has specific novelty, and can be used for preparing products for treating coronaviruses with wide practicability.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of forsythoside F in preparation of an anti-coronavirus product.
Background
Viruses are DNA or RNA surrounded by a protective shell, and clinical symptoms are acute hyperthermia, systemic pain, significant debilitation and respiratory symptoms. Coronaviruses are currently known to be the largest genome viruses among RNA viruses, and the novel coronavirus, COVID-19, is currently known to be coronaviruses that can infect humans. Epidemiological hazards caused by susceptibility to coronaviruses have become an international concern for sudden public health events, and the current discovery of drugs against novel coronaviruses is a major challenge.
The novel coronavirus attacks humans mainly by expressing a complex of the RBD domain of the Spike protein with ACE2, 3CL hydrolase, RNA-dependent RNA polymerase and other proteins (Science, 2020, 368:779-782;Biochem J,2011, 436:53; science,2020, 367:1444-1448). The novel coronavirus Spike protein RBD structural domain and ACE2 complex, 3CL hydrolase, RNA-dependent RNA polymerase and the like are used as targets for molecular docking to find inhibitors, further the complex of S protein and ACE2 is blocked to inhibit the invasion of COVID-19 on human body, kinetic measurement of affinity parameters is adopted, and cell experiments are adopted to detect the virus inhibition capability, so that the novel coronavirus COVID-19 inhibitor is an important way for finding novel coronavirus COVID-19 inhibitors at present.
The novel complex of the RBD domain of the Spike protein of the coronavirus and ACE2, 3CL hydrolase, RNA-dependent RNA polymerase and the like are used as target proteins for molecular docking, dynamic measurement of affinity parameters is adopted, and cell experiments are adopted to detect the virus inhibition capability, so that the inhibitor of the coronavirus is found from natural plants. The inventor discovers a compound forsythoside F with obvious inhibition activity.
Forsythoside F belongs to caffeoyl phenethyl alcohol glycoside compounds, and is mainly found in plants of the Oleaceae family and the like (molecular, 2009, 14:1324; chinese natural medicine, 2014, 12:697).
At present, no research report on the antiviral effect of forsythoside F is found.
Disclosure of Invention
The invention uses molecular docking, affinity measurement and cell inhibition experiment as means for finding coronavirus inhibitor. The novel complex of coronavirus S protein and ACE2 is adopted as target protein for molecular docking, kinetic measurement of affinity parameters is adopted, the virus inhibition capacity is detected by adopting a cell experiment, and the forsythoside F is found to have obvious inhibition effect on coronaviruses from natural plants.
The invention aims to provide application of forsythoside F in preparation of coronavirus products.
Forsythoside F is a compound shown in figure 1.
The forsythoside F has stronger affinity with ACE2, and can be applied to preparing a coronavirus inhibiting preparation by inhibiting the combination of coronavirus S protein and ACE 2.
The invention adopts molecular docking, kinetic measurement and cell antiviral experiment to evaluate the inhibition effect of forsythoside F on coronavirus, and the forsythoside F can be inhibited in a dose-dependent manner. Cell experiments are adopted to evaluate the antiviral effect of the forsythoside F, and the forsythoside F has remarkable inhibition effect on coronaviruses.
The application of forsythoside F in preparing antiviral products has the advantages of definite action mechanism and obvious inhibition effect. Forsythoside F can be isolated from plants of Oleaceae, etc.
The invention provides a forsythoside F and a pharmaceutical preparation thereof: injection, emulsion for injection, lyophilized powder for injection, oral liquid, aerosol, tablet, sugar coated tablet, film coated tablet, enteric coated tablet, effervescent tablet, sublingual tablet, capsule, hard capsule, soft capsule, microcapsule, microsphere, granule, pill, drop pill, powder, paste, suspension, solution, and sustained-release or controlled-release preparation.
Drawings
Fig. 1: the structure diagram of forsythoside F of the invention
Fig. 2: molecular docking diagram of example 1 of the present invention
Fig. 3: affinity diagram of inventive example 4
Fig. 4: affinity diagram of inventive example 5.
Detailed Description
Example 1 molecular docking Using novel coronavirus 3CL hydrolase as target protein
The PDB database downloads novel coronavirus 3CL hydrolase into PDB format, removes solvent, hydrogenates Autodock tools-1.5.6 software, combines nonpolar hydrogen, calculates charge, and stores the result as a receptor parameter file in Pdbqt format. And drawing a 2D structure of the small molecule ligand through Chem3D, generating the molecular 3D structure by using Chem3D software, performing energy minimization, storing all the used small molecule ligand into a mol2 format, and finally generating a ligand parameter file in a Pdbqt format. Autodocktools-1.5.6 software sets the lattice parameters of the receptor protein and sets the parameter text file. The autopackvina software is used for batch butt joint in a linux virtual environment, and the butt joint result shows that forsythoside F and novel coronavirus 3CL hydrolase have obvious combination, and the combination free energy is 65.51 Kcal/mol.
Example 2 molecular docking of novel coronavirus S protein and ACE2 Complex as target proteins
The PDB database downloads ACE2-RBD domain structure as PDB format, and the pymol software removes the solvent in the receptor protein, hydrogenates, combines nonpolar hydrogen, calculates charge and saves the charge as a receptor parameter file in Pdbqt format. The 2D structure of the small molecule ligand is drawn through Chem3D, the Chem3D software is used for generating the molecular 3D structure, energy minimization is carried out, and all the small molecule ligands are stored in a mol2 format. And giving the ligand atom types and calculating charges by means of a script file of Autodocktools-1.5.6, and finally generating a ligand parameter file in a Pdbqt format. Autodocktools-1.5.6 software sets the lattice parameters of the receptor protein and sets the parameter text file. Batch butt joint is performed under a linux virtual environment by using Autodock vina software, and when a butt joint result is obtained, forsythoside F can be embedded into a binding pocket of a complex of S protein and ACE2, and the binding free energy is 8.41 Kcal/mol.
Example 3 1 molecular docking Using novel coronavirus RNA-dependent RNA polymerase as target protein
The PDB database downloads RNA-dependent RNA polymerase for removing the solvent in the acceptor protein in the PDB format, hydrogenating, combining nonpolar hydrogen, calculating charge and storing as an acceptor parameter file in the Pdbqt format. The small molecule ligand 2D structure was drawn by Chem3D, and the Chem3D software was used to generate the molecular 3D structure, energy minimization, saved as a mol2 format. And giving the ligand atom types and calculating charges by means of a script file of Autodocktools-1.5.6, and finally generating a ligand parameter file in a Pdbqt format. Autodocktools-1.5.6 software sets the lattice parameters of the receptor protein and sets the parameter text file. The autopackvina software is used for batch butt joint in a linux virtual environment, and the pymol 1.7 Discovery Studio 3.5 software is used for carrying out visual analysis on the butt joint result. The docking result shows that the forsythoside F has obvious combination with the novel coronavirus RNA-dependent RNA polymerase, and the combination free energy is 12.26 Kcal/mol.
Example 4 use of kinetic assay for affinity parameters to the RBD Domain of S protein
The experimental chip was CM5 and the running buffer HEPES-EP+. Firstly, the S protein RBD domain is fixed on a CM5 chip, and after the protein is fixed on the surface of the chip, the affinity of an analyte and the protein is detected by adopting multicycle dynamics. Running 3 Startup cycles with running buffer instead of analyte sample before running the formal sample allows the system to simulate running sample at the beginning to reach stable baseline and system conditions. Analyte concentration gradients of 625, 1250, 2500, 5000, 10000 μm, flow rates of 30 μl/min, binding times of 180 s, dissociation of 320 s.0.75 mM NaOH was regenerated at 30 s at a flow rate of 20. Mu.L/min and after regeneration was stabilized at 60 s. Experimental results show that forsythoside F has stronger affinity with the S protein RBD domain within the range of 15 mu M to 500 mu M.
Example 5 use of kinetic measurements for affinity parameters with ACE2
The experimental chip was CM5 and the running buffer HEPES-EP+. ACE2 was first immobilized on CM5 chips and after the proteins were immobilized on the chip surface, the affinity of the analyte to the proteins was detected using multicyclic kinetics. Running 3 Startup cycles with running buffer instead of analyte sample before running the formal sample allows the system to simulate running sample at the beginning to reach stable baseline and system conditions. Analyte concentration gradients of 625, 1250, 2500, 5000, 10000 μm, flow rates of 30 μl/min, binding times of 180 s, dissociation of 320 s.0.75 mM NaOH was regenerated at 30 s at a flow rate of 20. Mu.L/min and after regeneration was stabilized at 60 s. Experimental results show that forsythoside F has strong affinity with ACE2 in the range of 15 mu M to 500 mu M.
Example 6 detection of Virus inhibition Capacity Using a cell experiment
The Vero9 cells were plated in 96-well plates for 24 hours, each well was inoculated with 50. Mu.l of 100 TCID50 virus solution, adsorbed at 37℃for 90 min, and the virus supernatant was discarded. According to the result of cytotoxicity experiment, adding different concentration of medicine in non-toxic concentration range, and setting normal cell control group and virus control group. The anti-culture plate was then placed at 37℃with 5% CO 2 Culture, daily observations of CPE. CPE recording method is [1 ]]CPE-free; + CPE in 25% of cells; ++ is 50% of cells present CPE; ++ + is that 75 percent of CPE appears in cells; ++ + + and 100 percent of cells present CPE. About the virus control++ to about when the process is carried out in the++ mode by using the MTT method, OD values at 570nm of each well were measured, and the inhibition rate of the drug to the virus is calculated according to the following formula. Viral inhibition = (drug treatment OD value-virus control OD value)/(cell control OD value-virus control OD value) ×100%. Experimental results show that forsythoside F has remarkable inhibition effect on coronaviruses within the range of 1 mu M to 100 mu M, and the effect and the dose show a dose-to-dose relationship.
Claims (8)
1. The application of forsythoside F as the only active ingredient in preparing an anti-novel coronavirus product is characterized in that the forsythoside F is a compound with the following structure:
。
2. the use according to claim 1, characterized in that: the forsythoside F is a drug of pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
3. Use according to claim 1 or 2, characterized in that: the subject is a human, cat, dog, pig or chicken.
4. The use according to claim 2, characterized in that: the drug is administered orally as follows: tablets, capsules, microspheres, granules, pills, powders, oral liquids, suspensions and sustained or controlled release preparations.
5. The use according to claim 4, characterized in that: the tablet is sugar-coated tablet, film-coated tablet, enteric-coated tablet, effervescent tablet or sublingual tablet;
the capsule is hard capsule, soft capsule or microcapsule;
the pill is dripping pill.
6. The use according to claim 2, characterized in that: the drug is administered by inhalation: an aerosol.
7. The use according to claim 2, characterized in that: the drug is administered intravenously as follows: an injection.
8. The use according to claim 7, characterized in that: the injection is injection emulsion or freeze-dried powder injection.
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