CN115252605A - Application of compound in preparation of medicine for resisting Getavirus infection - Google Patents
Application of compound in preparation of medicine for resisting Getavirus infection Download PDFInfo
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- CN115252605A CN115252605A CN202210810432.3A CN202210810432A CN115252605A CN 115252605 A CN115252605 A CN 115252605A CN 202210810432 A CN202210810432 A CN 202210810432A CN 115252605 A CN115252605 A CN 115252605A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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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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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/60—In silico combinatorial chemistry
- G16C20/64—Screening of libraries
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- Crystallography & Structural Chemistry (AREA)
- Theoretical Computer Science (AREA)
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- Veterinary Medicine (AREA)
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Abstract
The invention discloses an application of a compound in preparing a medicine for resisting a Getavirus infection, wherein the medicine comprises a therapeutically effective amount of a compound shown as a formula I or pharmaceutically acceptable salt, isomer and solvate thereof. In addition, the compound of the formula I in the invention breaks the E1-E2 interaction of the Getavirus by combining with the E2 structural protein in the Getavirus, blocks the assembly of virus particles, further interferes with the virus infection and replication, has obvious curative effect on preventing or treating the Getavirus infection and is difficult to generate drug resistance.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of a compound in preparing a medicine for resisting a Getavirus infection.
Background
Getah virus (GETV) belongs to an insect-borne virus in the Semliki Forest virus group (SFV) of the genus alphavirus of the family togaviridae, and the SFV group further comprises Chikungunya virus (CHIKV), semliki Forest Virus (SFV), malay virus (Mayaro virus, MAYV), una virus (UNAV), babaru virus (Bebaru virus, BEBV) and onien virus (O' nyong-nyong virus, ONNV), wherein CHIKV, ONNV and MAYV have a very high incidence and mortality in susceptible people.
GETV was originally derived from mosquitoes, and was limited to horse and pig cases in 40 years of 1960-2000, but only 20 years of this century, and has been expanded to many animals such as cattle, sheep, dogs, kangaroos, foxes, wild birds, and rabbits, guinea pigs, rats, hamsters, and the frequency of clinical cases is also increasing. Even more alarming is the detection of anti-GETV antibodies in febrile patients and even in healthy people. Although no report about the onset of human infection exists so far, various serum epidemiological surveys at home and abroad show that GETV antibodies exist in human bodies, and indicate that the virus can infect the human bodies. Because various animals are infected and attacked and mosquitoes are generally toxic, the livestock such as pigs and the like in vast rural areas of China are in close contact with people, GETV is likely to be popular among people, and a great potential risk is likely to exist in future public health events.
Scientists use cryoelectron microscopy to study all types of virus nodules in the alphavirus genusThe foot step is never stopped, and the resolution is from
To
The viruses studied include Barmah Forest Virus (BFV), EEEV, WEEV, VEEV, CHIKV, SINV, MAYV, and the like. The density chart of the cryo-electron microscope of the currently resolved alphavirus shows that: alphaviruses have the same structural composition. Alphavirus RNA is hidden in a disordered state in an icosahedral core consisting of 240 copies of capsid (capsid). The exogenously protruding E1 and E2 structural proteins form heterodimers (80 copies of which form an icosahedral viral coat) that are attached to the capsid across the phospholipid membrane. And GETV is a single-stranded positive-stranded RNA virus with an envelope. Mature Galtavirus is a spherical particle of about 70nm, and the genome of about 11kb is composed of 2 Open Reading Frames (ORFs), and contains a code and a polyprotein, wherein the polyprotein at the N-terminal comprises 4 non-structural proteins (nsP 1, nsP2, nsP3 and nsP 4), and the polyprotein at the C-terminal consists of 5 structural proteins (capsid-E3-E2-6K-E1). The research on the Galta virus in the prior art mainly focuses on enhancing the transmission vector of GETV, the detection and monitoring of animal infection of pigs, horses, cattle and the like, the quarantine of imported livestock and finished products thereof and the like, and the currently reported literature also focuses on the detection of the Galta virus, the vaccine prevention and the like, and the research on the medicine for treating the Galta virus infection is almost not available, so that the medicine capable of effectively treating the Galta virus infection is still lacked. In addition, methods for screening drugs by using molecular docking software and scoring software exist in the prior art, but the screening results of the existing screening methods are inaccurate, the screening cannot be accurately performed, and the existing screening methods lack verification steps.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention aims to provide the application of the compound shown in the formula I or the pharmaceutically acceptable salt, isomer and solvate thereof in preparing the medicine for preventing and/or treating the Getaavirus infection;
the invention also aims to provide a pharmaceutical composition for preventing and/or treating the Getavirus infection.
The invention also aims to provide a method for screening compounds for preventing and/or treating the Getavirus infection.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides the application of a compound shown in a formula I or pharmaceutically acceptable salts, isomers and solvates thereof in preparing a medicament for preventing and/or treating the Getavirus infection,
wherein R is1Selected from Cl, F, br, H, C1～5Alkyl radical, C1～5An alkoxy group;
R2selected from H, cl, F, br, C1～5An alkyl group;
R3selected from F, cl, br, C1～5Alkyl or C1～5An alkoxycarbonyl group;
n is 0,1,2,3,4 or 5;
m is 0,1,2,3,4 or 5.
Preferably, said C1～5Alkyl is selected from-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH2CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH(CH3)CH2CH3、-CH(CH3)CH2CH2CH3、-CH2CH(CH3)CH2CH3、-CH2CH2CH(CH3)2、-CH(CH2CH3)2、-CH2C(CH3)3、-C(CH3)2CH2CH3、-CH(CH3)CH(CH3)2。
Preferably, said C1～5Alkoxy is selected from-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、-OCH2CH2CH2CH2CH3、-OCH(CH3)2、-OC(CH3)3、-OCH2CH(CH3)2、-OCH(CH3)CH2CH3、-OCH(CH3)CH2CH2CH3、-OCH2CH(CH3)CH2CH3、-OCH2CH2CH(CH3)2、-OCH(CH2CH3)2、-OCH2C(CH3)3、-OC(CH3)2CH2CH3、-OCH(CH3)CH(CH3)2。
Preferably, said C1～5Alkoxycarbonyl is selected from-COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH2CH2CH2CH3、-COOCH2CH2CH2CH2CH3、-COOCH(CH3)2、-COOC(CH3)3、-COOCH2CH(CH3)2、-COOCH(CH3)CH2CH3、-COOCH(CH3)CH2CH2CH3、-COOCH2CH(CH3)CH2CH3、-COOCH2CH2CH(CH3)2、-COOCH(CH2CH3)2、-COOCH2C(CH3)3、-COOC(CH3)2CH2CH3、-COOCH(CH3)CH(CH3)2。
Preferably, in formula I, R1Selected from Cl, F, br, H, C1～3Alkyl radical, C1～3An alkoxy group; further preferably, R1Selected from Cl, F, H, methyl and methoxy.
Preferably, in formula I, R2Selected from H, cl, F, br, C1～3An alkyl group; further preferably, R2Selected from H, cl, F, methyl.
Preferably, in formula I, R3Selected from F, cl, C1～3Alkyl or C1～3An alkoxycarbonyl group; further preferably, R3Selected from Cl, C1～3Alkyl or ethoxycarbonyl.
Preferably, in formula I, n is 0,1 or 2; further preferably, n is 0 or 1.
Preferably, in formula I, m is 0,1 or 2.
Preferably, said C1～3Alkyl is selected from-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2。
Preferably, said C1～3Alkoxy is selected from-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2。
Preferably, said C1～3Alkoxycarbonyl is selected from-COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH(CH3)2。
Preferably, the compound of formula I is selected from:
preferably, the compound of formula I is
Preferably, the compound in the formula I can be prepared by the following preparation method: the method comprises the following steps:
s1: make it
And CS2、ClCH2CO2Me reaction to obtain
Make it
And ClCH2COCl reaction to obtain
Then with R2By reaction of radical-substituted indolinediones to give
S2: make it
Mixing and reacting to obtain the compound shown in the formula I.
Preferably, the medicament comprises a therapeutically effective amount of a compound shown in formula I or pharmaceutically acceptable salts, isomers and solvates thereof.
Preferably, the medicament further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the medicament is in the form of pills, tablets, granules, capsules, syrups or injections.
The anti-Getavirus infection in the invention refers to a series of diseases caused by Getavirus infection which can be prevented or treated.
Solvate in the present invention means that the drug crystal contains solvent molecules.
Preferably, the gata virus is of bovine, ovine, canine, kangaroo, fox, avian, rabbit, guinea pig, rat or hamster origin.
The second aspect of the present invention provides a pharmaceutical composition for preventing and/or treating a Getavirus infection, comprising a therapeutically effective amount of a compound represented by formula I or a pharmaceutically acceptable salt, isomer, solvate thereof,
wherein R is1、R2、R3N, m are as defined above.
Preferably, the compound represented by the formula I is
Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
Preferably, the pharmaceutical composition is in the form of pills, tablets, granules, capsules, syrups or injections.
The term "therapeutically effective amount" means an amount of the agent of the invention sufficient to produce a beneficial or desired effect when administered to a human infected with a Galtavirus; the effect may be the prevention of a Galtaavirus infection and/or the treatment of clinical symptoms or indicators associated with a Galtaavirus infection. It will be appreciated, however, that the total daily amount of the medicament of the invention must be determined within the scope of sound medical judgment. For any particular infected subject, the particular therapeutically effective dose level will depend upon a variety of factors including the severity of the infection in the subject being treated; the activity of the particular drug employed; the specific drug or dosage form employed; body weight, general health, diet of the infected; the time of administration, route of administration and rate of excretion of the drug employed; the duration of treatment; drugs used in combination or concomitantly with the specific drug employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of drug at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved.
The term "pharmaceutically acceptable adjuvant" is a substance that is non-toxic, compatible with the active ingredient, and otherwise biologically applicable to the organism. The choice of a particular adjuvant will depend on the mode of administration or the type and state of the disease used to treat a particular patient. Examples of the pharmaceutically acceptable auxiliary materials include, but are not limited to, solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, antioxidants and the like which are conventional in the pharmaceutical field. If necessary, a flavor, a preservative, a sweetener, and the like may be further added to the pharmaceutical composition.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also included are Salts of amino acids such as arginine, etc., and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to either base or acid addition salts.
Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention wherein the parent compound is modified by salification with an acid or salification with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, or p-toluenesulfonic acid.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The "isomers" of the present invention include geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic and other mixtures thereof, all of which are within the scope of the present invention. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to one of the functional group isomers that has a different point of attachment of hydrogen by one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and a relationship between the molecules that is not a mirror image. The term "cis-trans isomers" refers to different spatial configurations in which a double bond or a single bond of a ring-forming carbon atom in a molecule does not rotate freely.
In the present invention, the substituent R3The definitions in each case are independent, and the substituents may be identical or different; in general, the variables may be selected from the same or different substituents of the same embodiment; for example, when m is 2 in formula (I), the phenyl ring is substituted by two R3Is substituted by radicals in which each R is3Are defined independently of each other.
A third aspect of the present invention provides a method for screening a compound for preventing and/or treating a togavirus infection, comprising the steps of:
s1: acquiring a mapping relation between antiviral molecules and antiviral characteristics, and constructing a model;
s2: screening a compound conforming to the model from the database to obtain a primary screened compound;
s3: taking the protein of the Getavirus as a substrate, taking an antiviral drug of the Reed-Sivir as a molecular probe, evaluating by using scoring software, and screening out a binding site from the protein of the Getavirus;
s4: and performing molecular docking on the preliminarily screened compound and the binding sites in the proteins of the Getavirus, and screening based on the binding parameters to obtain the target compound.
Preferably, the binding parameters include binding energy, conformation.
The conformation in the present invention refers to a spatial arrangement in a molecule, which is generated by the placement of atoms around a single bond without changing the structure of a covalent bond. No cleavage and reformation of covalent bonds is required to change from one conformation to another. The conformational change does not alter the optical activity of the molecule.
The formula for the binding energy is:
where the sum is for all pairs of atoms that can move relative to each other, typically no 1-4 interactions, i.e. atoms separated by 3 consecutive covalent bonds, are included. Here, each atom i is assigned a type tiAnd is and
is to define the distance (r) between atomsij) A set of symmetrical interaction functions.
The invention has the beneficial effects that: the compound of the formula I has excellent effect of preventing or treating the Getaavirus infection, has no obvious toxic or side effect on normal cells, and can achieve the effect of inhibiting the Getaavirus at lower concentration. In addition, the compound of the formula I in the invention breaks the E1-E2 interaction of the Getavirus by combining with the E2 structural protein in the Getavirus, blocks the assembly of virus particles, further interferes with the virus infection and replication, has obvious curative effect on preventing or treating the Getavirus infection and is difficult to generate drug resistance. Specifically, the compound of the formula I has obvious antiviral activity under the concentration of about 12.5 mu mol/L, and has no cytotoxicity in the concentration range of 3.125-50 mu mol/L.
The screening method is simple, easy to operate and high in screening accuracy and efficiency. In addition, the screening method carries out a verification step on the primary screened compound, specifically, a Capsid-E2-E1 structure is taken as a target, an antiviral drug Reidesvir is selected as a small molecular probe, a series of binding sites are screened from the Galavirus, and the compound for preventing and/or treating the Galavirus is screened out through the binding energy and the molecular conformation of the primary screened compound and the binding sites, so that the screened compound has good curative effect and accurate result.
Drawings
FIG. 1 shows a structural diagram of Cryo-EM of Getavirus of the present invention.
FIG. 2 is a graph showing the prediction of binding of Compound 1 of the present invention to a Galavirus protein.
FIG. 3 is a partially enlarged view of the binding site of Compound 1 to the Galavirus protein in FIG. 2.
FIG. 4 is a graph showing cytotoxicity test of Compound 1 of the present invention.
FIG. 5 is a graph showing the antiviral activity test of Compound 1 of the present invention.
Detailed Description
Specific embodiments of the present invention are described in further detail below with reference to the figures and examples, but the practice and protection of the present invention is not limited thereto. It is noted that the processes described below, if not specifically detailed, are all those that can be implemented or understood by those skilled in the art with reference to the prior art. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available by commercial purchase.
The invention utilizes Cryo-EM (frozen electron microscope) to carry out structural analysis on a GETV-V1 strain which can cause reproductive failure of pregnant female mice, and concretely relates to figure 1, wherein figure 1 (A) is an external surface diagram of a Gatta virus, and a cover can be seen from figure 1 (A)The tower virus outer surface has specified 5-, 3-and 2-fold axes of symmetry; FIG. 1 (B) is a sectional view of a Getavirus; FIG. 1 (C) is an electron density diagram of Getavirus; FIG. 1 (D) is an atomic model diagram of a Getavirus; FIG. 1 (E) is an atomic model of E1-E2-capsid heterotrimer. From
In the atomic resolution map, 19 newly identified interaction forces (hydrogen bonds or salt bridges) play an important role in maintaining the overall structure stability of the virus, 8 glycosylation sites which are found and built up an atomic model on the surface of particles are involved in receptor antibody recognition and virus immune escape, 5S-acylation sites (S-acylation sites) which are built up on an E1/E2 near an inner phospholipid membrane contribute to virus assembly and transmembrane region stabilization, and 1 Dioleoylphosphatidylcholine (DOPC) and 3 cholesterol which are identified in and near a hydrophobic pocket formed by a TM helix (transmembrane helical region) of E1, a TM helix (transmembrane helical region) of E2 and a domain D (D region) of E2 have great value in maintaining the structure stability of E1/E2, particularly the DOPC and the cholesterol in the pocket.
GETV virus consists of Capsid, E3, E2, 6K and E1:
amino acid sequence of Capsid (Capsid):
MNYIPTQTFYGRRWRPRPAYRPWRVPMQPAPPMVIPELQTPIVQAQQMQQLISAVSALTTKQNGKAPKKPKKKPQKAKAKKNEQQKKNENKKPPPKQKNPAKKKKPGKRERMCMKIENDCIFEVKLDGKVTGYACLVGDKVMKPAHVKGVIDNPDLAKLTYKKSSKYDLECAQIPVHMKSDASKYTHEKPEGHYNWHHGAVQYSGGRFTIPTGAGKPGDSGRPIFDNKGRVVAIVLGGANEGARTALSVVTWTKDMVTRYTPEGTEEW
amino acid sequence of E2:
SVTEHFNVYKATKPYLAYCADCGDGQFCYSPVAIEKIRDEASDGMIKIQVAAQIGINKGGTHEHNKIRYIAGHDMKEANRDSLQVYTSGVCAIRGTMGHFIVAYCPPGDELKVQFQDAESHTQACKVQYKHAPAPVGREKFTVRPHFGIEVPCTTYQLTTAPTEEEIDMHTPPDIPDITLLSQQSGNVKITAGGKTIRYNCTCGSGNVGTTSSDKTINSCKIAQCHAAVTNHDKWQYTSSFVPRADQLSRKGKVHVPFPLTNSTCRVPVARAPGVTYGKRELTVKLHPDHPTLLTYRSLGADPRPYEEWIDRYVERTIPVTEDGIEYRWGNNPPVRLWAQLTTEGKPHGWPHEIILYYYGLYPAATIAAVSAAGLAVVLSLLASCYMFATARRKCLTPYALTPGAVVPVTLGVLCCAPRAHA
amino acid sequence of E1:
YEHTATIPNVVGFPYKAHIERNGFSPMTLQLEVLGTSLEPTLNLEYITCEYKTVVPSPYIKCCGTSECRSMERPDYQCQVYTGVYPFMWGGAYCFCDTENTQLSEAYVDRSDVCKHDHAAAYKAHTAAMKATIRISYGNLNQTTTAFVNGEHTVTVGGSRFTFGPISTAWTPFDNKIVVYKNDVYNQDFPPYGSGQPGRFGDIQSRTVESKDLYANTALKLSRPSSGTVHVPYTQTPSGFKYWLKERGTSLNDKAPFGCVIKTNPVRAENCAVGNIPVSMDIPDTAFTRVIDAPAVTNLECQVAVCTHSSDFGGIATLTFKTDKPGKCAVHSHSNVATIQEAAVDIKTDGKITLHFSTASASPAFKVSVCSAKTTCTAACEPPKDHIVPYGASHNNQVFPDMSGTAMTWVQRVAGGLGGLTLAAVAVLILVTCVTMRR
the invention utilizes Cryo-EM (freezing electron microscope) to carry out structural analysis on GETV-V1 strains, thereby defining the structure of the Getavirus.
The invention is described in further detail below with reference to specific examples:
the invention provides a method for screening a compound for preventing and/or treating a Getaavirus infection, which comprises the following specific steps:
a method based on Geometric Deep Learning (Geometric Deep Learning) (developed by Suzhou Yunhao medicine science and technology Co., ltd.) is adopted, antiviral molecules which accord with commercial availability and chemical diversity are selected, a mapping relation between the existing antiviral molecules and antiviral properties is obtained, a screening model is constructed based on the mapping relation between the existing antiviral molecules and the antiviral properties, the model is a Deep Learning network (Graph-based Deep Learning), and then the screening model is used for predicting the antiviral properties of compounds in a large-scale molecular library so as to discover potential seedling-head compounds. And finally, performing molecular sequencing according to the predicted scores, selecting and screening the seedling-end compounds according to the predicted physicochemical properties, and finally performing molecular docking cross validation on the screened compounds.
The method for molecular docking cross-validation of the primarily screened compounds specifically comprises the following steps:
firstly, dividing three-dimensional space grids of proteins (sub 1, sub2, sub3, monomers and tetramers) in the Galtavirus, wherein the sub1, sub2 and sub3 are three sub domain names of E2 structural proteins in the Galtavirus proteins, the monomers are E1-E2-capsids, and the tetramers are assembled by four monomers, and the space between the three sub domain names is 20 angstroms. Then, by taking the grids as the center, taking 15 angstroms as the radius, selecting an antiviral drug namely the Rudeciclovir as a small molecular probe, and scoring by using docking software, thereby screening a series of binding sites. For each grid point, the score of the best binding posture among them was chosen as the assessment of the binding pocket for that site. And then, the binding sites are examined one by one, so that the final binding site is selected, and the binding site is a substrate binding groove and can be used for next large-scale small molecule library screening.
The biochemicals and LC antiviral small molecule libraries containing 10157 small molecules were then screened. For more than 700 ten thousand molecules of a more comprehensive small molecule library ZINC, 100 ten thousand molecules are randomly selected for molecular docking, 50 molecules with the highest score are screened out from an LC antiviral small molecule library and a ZINC library in total, similarity inspection is carried out on the remaining 600 molecules in the ZINC library, and in the inspection, the molecule with any similarity of 50 molecules larger than 0.6 can be selected for docking with a binding site in a protein of a togavirus. In these molecular docking, in order to increase computational efficiency, 5 conformation images were examined for each small molecule at the time of docking, scored using scoring software, and screened according to binding energy and molecular conformation, thereby screening compound 1 for preventing and/or treating a togavirus infection in the present invention.
Compound 1, molecular formula:
the chemical name is: 4- (2- {3- [ (5Z) -3- [ (2-chlorophenyl) methyl group]-4-oxo-2-sulfonamido-1,3-thiazolidin-5-ylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl } acetamide) ethyl benzoate having the formula: c29H22ClN3O5S2The CAS number of the compound is: 617696-38-5.
Further optimizing the molecular structure of the compound 1 to obtain compounds 2 to 59, wherein the molecular formulas of the compounds 2 to 59 are as follows:
then, the binding energies of the compounds 1 to 59 were calculated while predicting the binding of the above-mentioned compounds 1 to 59 to the proteins of the Getavirus, respectively, and the calculated binding energies of the compounds 1 to 59 are shown in Table 1 below:
TABLE 1 binding energies of Compounds 1 to 59
As is clear from Table 1, the binding energies of the compounds 1 to 59 were in the range of-7.9 to-9.8 kcal/mol, and it is found that the compounds 1 to 59 all have a good binding force to the proteins of the Getavirus.
All of compounds 1 to 59 are binding pockets to the D region (subdomain D) of the Galavirus located in the E2 protein, close to the hydrophobic pocket formed by the TM helix (transmembrane helix) and D regions of the E2 protein, the TM helix of the E1 protein. Studies indicate that the D region plays an important role in maintaining the stability of the hydrophobic pocket and also affects the release of lipids in the hydrophobic pocket and the large-scale conformational changes of the overall structure of E1-E2-Capsid. It is presumed that the compounds 1 to 59 disrupt the E1-E2 interaction, thereby inhibiting the assembly of viral particles and interfering with viral infection and replication.
According to the invention, the compounds 1-59 are combined with the proteins of the Galavirus, the combination position is predicted, and the analysis of the interaction of the predicted optimal combination conformation defines the action site on the protein, namely the specific position of the combination pocket. Among them, taking compound 1 as an example, the predicted optimal binding conformation for protein binding of compound 1 to the gata virus is shown in fig. 2 and 3. Specific different kinds of interactions are shown in tables 2 to 4 below:
TABLE 2 hydrophobic interaction site Generation of proteins and Compounds
| Serial number | Protein residues | AA (amino acid abbreviation) |
| 1 | 277 | |
| 2 | 279 | LYS |
| 3 | 320 | VAL |
| 4 | 337 | LEU |
| 5 | 338 | |
| 6 | 340 | GLN |
TABLE 3 sites of hydrogen bonding interaction of proteins with compounds
| Serial number | Protein residues | AA (amino acid abbreviation) |
| 1 | 338 | TRP |
TABLE 4 sites of pi-pi stacking interaction of proteins with compounds
| Serial number | Protein residues | AA (amino acid abbreviation) |
| 1 | 277 | TYR |
As can be seen from FIGS. 2 to 3 and tables 2 to 4, compound 1 has hydrophobic interactions with 277TYR,279LYS,320VAL,337LEU,338TRP and 340GLN, respectively; compound 1 and 338TRP have hydrogen bonding interactions; compound 1 and 277TYR form a pi-pi stacking interaction; therefore, the compound 1 of the present invention has a good binding property to the binding site in the protein of the togavirus.
Compound 1 was then tested for cytotoxicity and anti-togavirus activity as follows:
the CCK-8 kit was first used to evaluate the toxicity of the above compounds on cells cultured in vitro. The CCK-8 kit was purchased from Donjindo, and the cell viability of BHK21 cells treated with the above-described compounds was measured according to the protocol provided. BHK21 cells were seeded in a 96-well plate and cultured to 80% density of monolayer cells, then different concentrations of the above-mentioned compounds (concentration of the compounds: 50. Mu. Mol/L, 25. Mu. Mol/L, 12.5. Mu. Mol/L, 6.25. Mu. Mol/L, 3.125. Mu. Mol/L, respectively) were added to different wells as experimental groups, 0.1% DMSO was added to control groups, no compound or solvent was added to blank groups, after the cells of the experimental, control and blank groups were treated separately for 24h, CCK-8 solution was added to each well and further cultured at 37 ℃ for 2h. The absorbance at 450nm was measured using SPARK 10M (multifunctional microplate detector) and the results are shown in FIG. 4. As can be seen from FIG. 4, C was added at various concentrations (3.125. Mu. Mol/L to 50. Mu. Mol/L)29H22ClN3O5S2The difference between the absorbance at 450nm of the drug group and the absorbance at 450nm of the drug-free group is very small, which indicates that the compound C in the invention29H22ClN3O5S2The concentration of the compound is 3.125-50 mu mol/L, and the compound has no obvious toxicity to cells.
Subsequently, the antiviral activity of the above compounds was tested at the cellular level, using a method of fixing the viral load and mixing the same amount of serially diluted multiple compounds. BHK21 cells were seeded into 96-well plates and cultured to 80% density monolayers. According to 100TCID50Seeded Getah virus to per well finenessCells, incubated for 0.5h, virus fluid was discarded, and 100. Mu.L of the above-mentioned compounds were rapidly added to each well of cells at concentrations of 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.125. Mu.M (μ M appearing herein means. Mu. Mol/L), to thereby calculate CO at 5%2After incubation at 37 ℃ for 48h, the equation for Reed-Muench calculation (Reed-Muench calculation: distance ratio = (percentage higher than 50% disease rate-50%)/(percentage higher than 50% disease rate-percentage lower than 50%); "logTCID50= distance ratio x difference between the logarithm of dilutions + the logarithm of dilutions above 50% disease rate, dilution means concentration of compound 50 μ M,25 μ M,12.5 μ M,6.25 μ M,3.125 μ M) respectively) to measure TCID of GETV after effect of different concentrations of the above-mentioned compound50The relative quantification was determined, and the results are shown in FIG. 5, and it is clear from FIG. 5 that Compound C of the present invention29H22ClN3O5S2Has effect in inhibiting viral activity, meets basic application requirement as medicine, and is calculated by calculating the 100TCID of GETV50Value, C can be determined29H22ClN3O5S2The molecule has obvious antiviral activity at the concentration of 12.5 mu mol/L. In addition, data were processed and analyzed using one-way ANOVA in SPSS software<0.01 represents a very significant difference, specifically: transverse and x marked in dmso histograms compared to control group 0.1% mean significant differences, i.e. significant differences of 50 μ M,25 μ M and 12.5 μ M.
The binding force of the compounds 2 to 59 selected by the screening method of the present invention to the binding site on the protein of the Getavirus is the same as that of the compound 1 (C)29H22ClN3O5S2) And thus, the effects of compounds 2 to 59 in cytotoxicity and anti-gacovavirus activity were also at substantially the same level as that of compound 1.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (18)
1. The application of the compound shown in the formula I or the pharmaceutically acceptable salt, isomer and solvate thereof in preparing the medicine for preventing and/or treating the Getavirus infection,
wherein R is1Selected from Cl, F, br, H, C1～5Alkyl radical, C1～5An alkoxy group;
R2selected from H, cl, F, br, C1～5An alkyl group;
R3selected from F, cl, br, C1～5Alkyl or C1～5An alkoxycarbonyl group;
n is 0,1,2,3,4 or 5;
m is 0,1,2,3,4 or 5.
2. Use according to claim 1, characterized in that: in the formula I, R1Selected from Cl, F, br, H, C1～3Alkyl radical, C1～3An alkoxy group; preferably, R1Selected from Cl, F, H, methyl and methoxy.
3. Use according to claim 1, characterized in that: in the formula I, R2Selected from H, cl, F, br, C1～3An alkyl group; preferably, R2Selected from H, cl, F, methyl.
4. Use according to claim 1, characterized in that: in the formula I, R3Selected from F, cl, C1～3Alkyl or C1～3An alkoxycarbonyl group; preferably, R3Selected from Cl, C1～3Alkyl, ethoxycarbonyl.
5. Use according to claim 1, characterized in that: in the formula I, n is 0,1 or 2; preferably, n is 0 or 1.
6. Use according to claim 1, characterized in that: in formula I, m is 0,1 or 2.
7. Use according to claim 1, characterized in that: the compound of formula I is selected from:
8. use according to claim 7, characterized in that: the compound shown as the formula I is
9. Use according to any one of claims 1 to 8, characterized in that: the medicament comprises a therapeutically effective amount of a compound shown in formula I or pharmaceutically acceptable salts, isomers and solvates thereof.
10. Use according to claim 9, characterized in that: the medicine also comprises pharmaceutically acceptable auxiliary materials.
11. Use according to claim 9, characterized in that: the dosage form of the medicine is pills, tablets, granules, capsules, syrup or injection.
12. Use according to any one of claims 1 to 8, characterized in that: the Galtavirus is derived from a bovine, ovine, canine, kangaroo, fox, bird, rabbit, guinea pig, rat, or hamster.
13. Use according to any one of claims 1 to 8, characterized in that: the compound shown in the formula I is combined with an E2 structural protein in a Getavirus.
14. A pharmaceutical composition for the prevention and/or treatment of a togavirus infection, characterized in that: comprises a therapeutically effective amount of a compound shown as a formula I or pharmaceutically acceptable salts, isomers and solvates thereof,
wherein R is1、R2、R3N and m are as defined in any one of claims 1 to 6.
15. The pharmaceutical composition for the prevention and/or treatment of a Getaavirus infection according to claim 14, characterized in that: the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.
16. The pharmaceutical composition for the prevention and/or treatment of a Getaavirus infection according to claim 14, characterized in that: the dosage form of the pharmaceutical composition is pills, tablets, granules, capsules, syrup or injection.
17. A method of screening for a compound for the prevention and/or treatment of a togavirus infection comprising: the method comprises the following steps:
s1: acquiring a mapping relation between antiviral molecules and antiviral characteristics, and constructing a model;
s2: screening a compound conforming to the model from the database to obtain a primary screened compound;
s3: taking the protein of the Getavirus as a substrate, taking an antiviral drug of the Reed-Sivir as a molecular probe, evaluating by using scoring software, and screening out a binding site from the protein of the Getavirus;
s4: and performing molecular docking on the preliminarily screened compound and the binding sites in the proteins of the Getavirus, and screening based on the binding parameters to obtain the target compound.
18. The method of claim 17, wherein: the binding parameters include binding energy, conformation.
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| CN115844879A (en) * | 2023-02-27 | 2023-03-28 | 三亚南京农业大学研究院 | Application of melatonin in resisting Galavirus |
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