CN114246850A - Application of p-benzoquinone or derivatives thereof in preparation of anti-coronavirus medicines and medicines - Google Patents
Application of p-benzoquinone or derivatives thereof in preparation of anti-coronavirus medicines and medicines Download PDFInfo
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- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 229940079593 drug Drugs 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 241000711573 Coronaviridae Species 0.000 claims abstract description 34
- 101800000535 3C-like proteinase Proteins 0.000 claims abstract description 10
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 claims abstract description 10
- 208000001528 Coronaviridae Infections Diseases 0.000 claims abstract description 7
- 239000003112 inhibitor Substances 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 18
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 4
- 241000315672 SARS coronavirus Species 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 241000711467 Human coronavirus 229E Species 0.000 claims description 3
- 241000482741 Human coronavirus NL63 Species 0.000 claims description 3
- 241001428935 Human coronavirus OC43 Species 0.000 claims description 3
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000013078 crystal Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 102000004190 Enzymes Human genes 0.000 abstract description 5
- 108090000790 Enzymes Proteins 0.000 abstract description 5
- 101800000504 3C-like protease Proteins 0.000 description 17
- KEQHJBNSCLWCAE-UHFFFAOYSA-N thymoquinone Chemical compound CC(C)C1=CC(=O)C(C)=CC1=O KEQHJBNSCLWCAE-UHFFFAOYSA-N 0.000 description 17
- 108091005804 Peptidases Proteins 0.000 description 11
- 239000004365 Protease Substances 0.000 description 11
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 101800001016 Picornain 3C-like protease Proteins 0.000 description 9
- 101800000596 Probable picornain 3C-like protease Proteins 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 238000000034 method Methods 0.000 description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- 229910021538 borax Inorganic materials 0.000 description 5
- 239000004328 sodium tetraborate Substances 0.000 description 5
- 235000010339 sodium tetraborate Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- 208000009525 Myocarditis Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 101800000508 Non-structural protein 5 Proteins 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 101710153041 Replicase polyprotein 1a Proteins 0.000 description 1
- 101710151619 Replicase polyprotein 1ab Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- -1 adsorption carrier Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 208000020470 nervous system symptom Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
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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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to application of p-benzoquinone and derivatives thereof in preparation of a coronavirus infection resistant medicament. The p-benzoquinone and the derivatives thereof have strong inhibition effect on the enzyme activity of the target main protease 3Clpro of coronavirus, especially novel coronavirus, and can be used for preparing a medicine for resisting coronavirus, especially novel coronavirus infection.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to application of p-benzoquinone and derivatives thereof in preparation of a coronavirus infection resistant medicament.
Background
Coronaviruses belong to the single positive strand RNA virus, and the family of coronaviruses mainly includes novel coronaviruses (SARS-CoV-2), SARS coronaviruses (SARS-CoV), middle east respiratory syndrome coronaviruses (MERS-CoV), HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU. Coronaviruses commonly cause respiratory and intestinal diseases, neurological symptoms, and myocarditis. The infection of these diseases seriously affects the health of people. The repeated outbreaks of coronaviruses suggest that human beings have little knowledge about their studies, and the development of drugs for treating new coronaviruses is imminent.
The main protease of coronavirus, also called 3C-like protease (3CLpro), is a hydrolase expressed in the genome nsp5 at the 5' end of coronavirus and mainly functions to cleave at least 11 sites on the polyproteins pp1a and pp1ab, which need to be processed into mature functional protein after being hydrolyzed; the 3C-like protease (3CLpro) is a cysteine protease that recognizes sequences with Leu and Glin at positions P2 and P1, respectively. In addition, the substrate binding site of the 3C-like protease (3CLpro) is highly conserved and plays a key role in mediating virus replication and transcription, so the 3CL protease can be used as an ideal target point for designing and screening the anti-coronavirus medicines.
P-benzoquinone and its derivatives are typical Michael acceptor structures, can react with cysteine sulfydryl, can act as a free radical scavenger, and can protect enzymatic activities of catalase, glutathione peroxidase and glutathione S-transferase from being damaged. We are keenly aware that the michael acceptor structure of p-benzoquinone and its derivatives may inhibit the activity of cysteine proteases, where we demonstrate that p-benzoquinone and its derivatives can inhibit the enzymatic activity of the major protease 3Clpro of coronaviruses, especially novel coronaviruses. Through examining the relevant data, no report about p-benzoquinone and its derivatives as the inhibitor of the coronavirus main protease 3Clpro is found.
Disclosure of Invention
The invention aims at the problem that relevant inflammatory diseases such as lung, respiratory tract and intestinal tract diseases, nervous system symptoms, myocarditis and the like caused by coronavirus lack of effective prevention and treatment medicines, and points out the application of p-benzoquinone and derivatives thereof in preparing anti-coronavirus inflammatory medicines.
The invention aims to provide p-benzoquinone and derivatives thereof serving as inhibitors of coronavirus 3C-like protease (3CLpro) and application thereof in preparing medicaments for preventing and/or treating novel coronavirus infection. The technology of the invention is based on the three-dimensional structure of the novel coronavirus 3CLpro to carry out drug design, and thousands of compounds including a natural product library, a clinical compound library and an antiviral drug library are virtually screened to obtain the compound which can possibly inhibit the novel coronavirus 3 CLpro. We then performed enzyme activity assays using a commercially available 3CLpro fluorescent probe construction method and used for inhibitor screening.
By screening the medicines according to the scheme, the invention discovers that the compounds shown in the following general formula 1 have the inhibition effect on SARS-CoV-23 CL protease:
wherein R is1-4Can be hydrogen, methyl, ethyl, propyl, isopropyl or halogen;
wherein R is1-4 must be one hydrogen.
Preferably, the compound of formula 1 may be thymoquinone (formula 2),
Drawings
FIG. 1 is a graph of the trend of the fluorescence intensity of the substrate peptide at different concentrations of the inhibitor thymoquinone of example 1 over time in 3C-like protease metabolism
Figure 2 is a graph of the inhibition of the novel coronavirus 3C-like protease by thymoquinone, an inhibitor of example 2.
Detailed Description
In order to illustrate the invention more clearly, the following examples are given for the purpose of illustrating the invention more clearly and are not to be construed as limiting the invention.
In carrying out the experiment, all the procedures and procedures, reaction conditions of the substrate, and the like are designed and carried out according to methods well known to those skilled in the art.
In the examples below, we used inhibitor molecules, available from mce (medchemexpress) or other common commercial sources.
SARS-Cov-23C-like protease used in the present invention is purchased from CrystalO Biopharma, substrate Dabcyl-KTSAVLQ ↓ SGFRKM-E (Edans) -NH2 is purchased from GL biochem, borax borate buffer is purchased from Lei root organism.
Preferably, SARS-Cov-23C-like protease (concentration is 0.1mg/mL), substrate peptide Dabcyl-KTSAVLQ ↓ ] SGFRKM-E (Edans) — NH2 (concentration is 0.1mM-5mM), borax borate buffer solution (pH ═ 5-8), the concentration of the borax borate buffer solution is 10-100 millimole/liter.
The invention requires fluorescence detection with a fluorescence microplate reader.
Example 1: measurement of inhibitory Activity of thymoquinone against SARS-Cov-23C-like protease
The specific implementation process comprises the following steps:
1) storing the SARS-Cov-23C-like protease and substrate peptide stock solution in a refrigerator at-80 ℃;
2) thawing SARS-Cov-23C-like protease (concentration 0.1mg/mL) in a frozen plate (-4 to 4 ℃) at room temperature, diluting 1uL in 98uL borax borate buffer (pH 7.4), and adding into the detection plate;
3) adding 1uL of inhibitor (thymoquinone, concentration of 0, 0.025mM, 0.125mM, 0.25mM, 0.5mM, 1mM, 2.5mM) into the solution obtained in step (2);
4) adding 1uL of substrate peptide (0.5mM) with the same concentration into the solution obtained in the step (3), incubating at 37 ℃ by using a fluorescence microplate reader, monitoring 342nm excitation by using the fluorescence microplate reader, detecting the fluorescence emission value at 496nm while incubating, and taking one point every 1 minute;
5) the slow increase effect of the fluorescence intensity of the substrate peptide in the enzyme metabolism with time in the presence of different concentrations of the inhibitor is shown in FIG. 1 below, and the results show that the fluorescence increase of the substrate peptide in the enzyme metabolism can be inhibited by the inhibitor thymoquinone, and that the inhibition effect is increased with the increase of the inhibitor concentration.
Example 2: measurement of inhibitory Capacity of thymoquinone against SARS-Cov-23C-like protease
The specific implementation process is as follows:
1) storing the SARS-Cov-23C-like protease and substrate peptide stock solution in a refrigerator at-80 ℃;
2) thawing SARS-Cov-23C-like protease (concentration 0.1mg/mL) in a frozen plate (-4 to 4 ℃) at room temperature, diluting 1uL in 98uL borax borate buffer (pH 7.4), and adding to the detection plate;
3) adding 1uL of inhibitor (thymoquinone, concentration of 0, 0.025mM, 0.125mM, 0.25mM, 0.5mM, 1mM, 2.5mM) into the solution obtained in step (2);
4) adding 1uL of substrate peptide (0.5mM) with the same concentration into the solution obtained in the step (3), incubating at 37 ℃ by using a fluorescence microplate reader, monitoring 342nm excitation by using the fluorescence microplate reader, detecting the fluorescence emission value at 496nm while incubating, and incubating for 1 h;
5) and counting the fluorescence emission value at 496nm after 342nm excitation before and after incubation of each group. The fluorescence change values before and after incubation of the control group (inhibitor concentration 0 group) were taken as 100, and the fluorescence change values before and after incubation of the different inhibition groups were compared to obtain the residual activity value (residual activity). The IC of the inhibitor was obtained as shown in FIG. two by plotting the logarithm of the inhibitor concentration (logC (inhibitor)) as the abscissa and the corresponding Residual Activity (Residual Activity) as the ordinate using GraphPad Prism6 software50The value is obtained. Table 1 lists the data on the inhibition activity of Compound 1 against SARS-Cov-23 CLpro. IC (integrated circuit)50The formula is calculated as Y ═ 100/(1+10^ ((X-LogIC50))), where Y represents the residual activity fraction, X represents the common logarithm of the concentration of inhibitor compound, and Λ refers to the power method. FIG. 2 is a graph showing the ratio of the concentration of various inhibitors to the activity of the inhibitory enzyme, and the inhibitory activity of the compound can be obtained as expressed by the concentration of the inhibitor at which the activity of the inhibitor is half inhibited.
Table one: thymoquinone structure and IC for inhibiting novel coronavirus 3C-like protease (3CLpro)50Value of
The p-benzoquinone and the derivatives thereof have strong inhibition effect on the enzyme activity of the target main protease 3Clpro of the coronavirus, particularly the novel coronavirus, and can be used for preparing the medicine for resisting the coronavirus, particularly the novel coronavirus infection.
Claims (10)
1. The application of p-benzoquinone or derivatives thereof (compounds in a formula 1) in preparing anti-coronavirus medicines.
2. The use according to claim 1, wherein the p-benzoquinone or its derivative comprises one or more compounds having the structure shown in formula 1 and pharmaceutically acceptable salts thereof,
wherein R is1、R2、R3、R4Can be hydrogen, methyl, ethyl, propyl, isopropyl or halogen (one of F, Cl, Br and I);
and, R1、R2、R3、R4Of which one must be hydrogen.
3. The use of a compound according to claim 1 or 2, wherein the benzoquinone or derivative thereof inhibits the enzymatic activity of the coronavirus main protease 3 Clpro.
4. Use of a compound according to claim 1 or 2, wherein p-benzoquinone or a derivative thereof is used for the manufacture of a medicament as an inhibitor of the coronavirus main protease 3 Clpro.
5. Use of a compound according to claim 1 or 2, wherein the coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, or a novel coronavirus (SARS-CoV-2).
6. The coronavirus according to claim 5, which is preferably a novel coronavirus (SARS-CoV-2).
7. The compound of formula 1 according to claim 1 or 2, wherein the compound of formula 1 comprises one or more of optical isomers thereof, hydrates thereof; the number of crystal water of the hydrate is any real number in the range of 1-16, and is preferably an integer.
8. A medicament for preventing and/or treating coronavirus infection or inflammation caused thereby,
comprises one or more than two of p-benzoquinone or derivatives thereof and pharmaceutically acceptable salts thereof.
9. An inhibitor drug for coronavirus main protease 3Clpro, which is characterized by comprising one or more than two of p-benzoquinone or a derivative thereof and a pharmaceutically acceptable salt thereof.
10. The medicament of claim 8 or 9, wherein the medicament is an injection, a tablet, a pill, a capsule, a suspension, a granule, a spray or an emulsion.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023019614A1 (en) * | 2021-08-19 | 2023-02-23 | 山东达因海洋生物制药股份有限公司 | Use of p-benzoquinone and/or derivative thereof in preparation of anti novel-coronavirus drug |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100273893A1 (en) * | 2009-04-23 | 2010-10-28 | Alkharfy Khalid M | Protective effect of thymoquinone in spesis |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100273893A1 (en) * | 2009-04-23 | 2010-10-28 | Alkharfy Khalid M | Protective effect of thymoquinone in spesis |
Non-Patent Citations (2)
| Title |
|---|
| BOUCHENTOUF SALIM等: "Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus （Covid-19）: Molecular Docking Study", 《BIOLOGICAL AND MEDICINAL CHEMISTRY》 * |
| YOUNESS KADIL等: "In silico Investigation of the SARS CoV2 Protease with Thymoquinone, the Major Constituent of Nigella Sativa", 《CURRENT DRUG DISCOVERY TECHNOLOGIES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023019614A1 (en) * | 2021-08-19 | 2023-02-23 | 山东达因海洋生物制药股份有限公司 | Use of p-benzoquinone and/or derivative thereof in preparation of anti novel-coronavirus drug |
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Application publication date: 20220329 |