CN114283902A - Screening method and screening system for pharmaceutical composition and electronic device - Google Patents

Abstract

The invention provides a screening method of a pharmaceutical composition, which comprises the following steps: step 1), acquiring a first model of a target disease and NES values of related pathways thereof; obtaining a target drug composition, and obtaining NES values of each single drug in the target drug composition on a first model and related pathways thereof; and 2) determining first pathway reversal data of a first model of the target disease and related pathways of the target drug composition, and screening according to the first pathway reversal data to obtain the drug composition. The invention also provides a screening system and electronic equipment for the pharmaceutical composition. The method provided by the invention utilizes the relevant knowledge of biomedicine and in-vitro experimental data, and carries out the combination evaluation of a large number of candidate single medicaments and the creation of new medicaments of the medicinal composition on the basis of the influence of the single medicament on the gene expression of different models, does not need to carry out basic research on a large number of Chinese medicinal components, and has lower cost and more accurate result.

Description

Screening method and screening system for pharmaceutical composition and electronic device

Technical Field

The invention relates to the technical field of drug compounding, in particular to a screening method and a screening system of a drug composition and electronic equipment.

Background

The traditional Chinese medicine is a treasure of Chinese nationality, and once and continuously makes irreplaceable contribution to the survival and health of Chinese people. The modernization of traditional Chinese medicine is to fully utilize the theory, method and means of modern scientific technology on the basis of inheriting and developing the advantages and characteristics of traditional Chinese medicine, and study, develop, manage and produce safe, efficient, stable and controllable modern traditional Chinese medicine products by referring to international current medical standards and specifications. Although China has strengthened the great strategy of developing the pharmaceutical industry by modern research and industrial development of traditional Chinese medicines, no efficient method and technology exist for large-scale system standardization of abundant medicinal material resources and a large number of traditional Chinese medicines (formulas); in modern traditional Chinese medicine creation, no efficient way is found.

In the research and development of new compound Chinese medicine, the development is carried out in a mode of 'inheriting tradition', namely, the new compound Chinese medicine is developed on the basis of the characteristics of the traditional Chinese medicine compound. With the deep research of Chinese medicine theory in recent years, the component Chinese medicine is a new medicine research and development form which is provided on the basis of gradually and deeply understanding the substance basis and action principle of the Chinese medicine, namely, under the guidance of Chinese medicine efficacy component theory, the component Chinese medicine new medicine is researched and developed on the basis of the traditional prescription and proved prescription. The component Chinese medicine method is based on the Chinese medicine theory, follows the compatibility theory and principle of Chinese medicine prescription, and is a modern Chinese medicine prepared by the compatibility of effective components. The component Chinese medicine method generally needs to establish a perfect traditional and modern information database related to Chinese medicinal materials, prescriptions and the like, wherein the medicament creation premise is to establish a standard component library, take components as links, and establish a development mode of component compatibility by using a system biology technology according to the thought of multi-component multi-target synergy on the basis of component standardization.

The existing component traditional Chinese medicine method firstly needs to carry out a large amount of basic research on traditional Chinese medicines and traditional Chinese medicine formulas, establish a component library, carry out work such as component preparation, component information system and activity screening, separate and research different functional components, and then carry out work such as component compatibility optimization design. However, the traditional Chinese medicine components are extremely complex, the complexity is that the components with different properties are large in quantity, large in structural difference and obvious in content difference from macromolecules to micromolecules, from water-soluble components to fat-soluble components and from inorganic substances to organic substances, and the traditional Chinese medicine is a complex black box system. At present, a High Performance Liquid Chromatography (HPLC) platform is generally used to combine with other multidimensional measuring instruments to directly carry out component analysis on a crude Chinese medicine extract, however, in many cases, the detection methods can cause that key components which really play the drug effect cannot be separated. In addition, because the traditional Chinese medicine components are complex, a large amount of capital is required to be invested in the component analysis process, and the labor cost and the time cost are high. Moreover, the action target of the compatibility of the traditional Chinese medicine compound is complex, particularly, the effective components screened by the component traditional Chinese medicine method are not bound with receptors but exert functions by interacting with other components or influencing the microenvironment of cells, and the problem of insufficient reaction of biological effect target points may exist in the compatibility directly through the components.

Disclosure of Invention

In view of this, the present invention aims to provide a screening method, a screening system and an electronic device for pharmaceutical compositions, and the screening method and the screening system provided by the present invention have high reliability and strong repeatability.

The invention provides a screening method of a pharmaceutical composition, which comprises the following steps:

step 1), acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database; the disease biological expression database comprises normalized enrichment score values of different diseases in different pathways of different models;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database; the drug efficacy database comprises standardized enrichment score values of different pathways of a single drug to different models;

and 2) determining first pathway reversal data of a first model of the target disease and related pathways of the target drug composition, and screening according to the first pathway reversal data to obtain the drug composition.

In one embodiment, the screening method further comprises:

step 3), acquiring a second model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

obtaining the standardized enrichment score values of each single drug in the pharmaceutical composition obtained in the step 2) on the second model and the related passages thereof from a pre-established drug efficacy database;

and 4) determining second channel reversal data of the second model of the target disease and the related channels of the pharmaceutical composition screened in the step 2), and screening according to the second channel reversal data to obtain the pharmaceutical composition.

In one embodiment, the screening method further comprises:

step 5), acquiring a third model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring the standardized enrichment score values of each single drug in the pharmaceutical composition obtained in the step 4) on the third model and the related passages thereof from a pre-established drug efficacy database;

and 6) determining third channel reversal data of the third model of the target disease and the related channels of the pharmaceutical composition screened in the step 4), and screening according to the third channel reversal data to obtain the pharmaceutical composition.

In one embodiment, the first model is a first cell line model, the second model is a second cell line model, and the third model is a third cell line model;

or, the first model is a first animal model, the second model is a second animal model, and the third model is a third animal model.

In one embodiment, the first path reversal data is a first path reversal rate, the second path reversal data is a second path reversal rate, and the third path reversal data is a third path reversal rate;

or the first channel reversal data is a first channel reversal number, the second channel reversal data is a second channel reversal number, and the third channel reversal data is a third channel reversal number.

In one embodiment, the path inversion rate is calculated according to formula (I):

P_reverse＝N_reverse/N_totalformula (I);

in the formula (I), P_reverseIndicates the path inversion rate, N_reverseRepresenting the number of reversal pathways, N, of the pharmaceutical composition in the corresponding model_totalRepresenting the number of pathways associated with the corresponding model and the target disease;

said N is_reverseCalculated according to formula (II) and formula (III):

in formula (II) and formula (III), i represents the ith pathway of the corresponding model, p represents the p pathways shared by the disease of interest on the corresponding model, NES_herbRepresents the normalized enrichment score, NES, of the pharmaceutical composition to be evaluated on the ith pathway_diseaseRepresents a normalized enrichment score value for the disease of interest on the ith pathway;

the NES_herbCalculated according to formula (V):

in the formula (V), m represents m single medicines in the medicinal composition, j represents the jth single medicine in the medicinal composition, Snes_jiMeans of the j-th singlenessNormalized enrichment score of drug on ith pathway.

In one embodiment, the single drug is a single herb or a single herb extract; the pharmaceutical composition is a Chinese herbal compound.

The invention also provides a screening system of the pharmaceutical composition, which comprises:

the first target disease information acquisition module is used for acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

the target drug acquisition module is used for acquiring a target drug composition and acquiring the standardized enrichment score values of each single drug in the target drug composition on the first model and the relevant passages thereof from a pre-established drug efficacy database;

the first analysis and screening module is used for determining first passage reversal data of a first model of the target disease and related passages of the target drug composition, and screening the target drug composition according to the first passage reversal data to obtain the drug composition.

In one embodiment, the screening system further comprises:

the second target disease information acquisition module is used for acquiring a second model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

the second drug information acquisition module is used for acquiring the standardized enrichment score values of each single drug in the drug composition obtained by the first analysis and screening module on the second model and the related passages from a pre-established drug efficacy database;

and the second analysis and screening module is used for determining second channel reversal data of the second model of the target disease and the related channel of the pharmaceutical composition screened by the first analysis and screening module, and screening the pharmaceutical composition according to the second channel reversal data.

In one embodiment, the screening system further comprises:

the third target disease information acquisition module is used for acquiring a third model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

the third medicine information acquisition module is used for acquiring the standardized enrichment score values of each single medicine in the medicine composition obtained by the second analysis and screening module on the second model and the related passages from a pre-established medicine efficacy database;

and the third analysis and screening module is used for determining third channel reversal data of the third model of the target disease and the related channels of the pharmaceutical composition obtained by screening of the second analysis and screening module, and screening the pharmaceutical composition according to the third channel reversal data.

The invention also provides an electronic device for screening a pharmaceutical composition, comprising a memory and a processor;

wherein the memory is used for storing programs;

the processor calls a program and is used to:

acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database;

determining first pathway reversal data of a first model of the target medicine composition on the target disease and relevant pathways of the target disease, and screening according to the first pathway reversal data to obtain the medicine composition.

The screening method of the pharmaceutical composition provided by the invention comprises the following steps of firstly, obtaining a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database; then obtaining the standardized enrichment score values of the target drug composition and each single drug in the target drug composition on the first model and relevant pathways of the first model; and finally, determining first channel reversal data of a first model of the target disease and related channels of the target drug composition, and screening according to the first channel reversal data to obtain the drug composition. The method provided by the invention utilizes the relevant knowledge of biomedicine and in-vitro experimental data, and carries out the combination evaluation of a large number of candidate single medicaments and the creation of new medicaments of the medicinal composition on the basis of the influence of the single medicament on the gene expression of different models, does not need to carry out basic research on a large number of Chinese medicinal components, and has lower cost and more accurate result.

Furthermore, the method provided by the invention is verified by combining 2 or more than 2 types of model gene expression profile data, and has high reliability and strong repeatability.

Drawings

FIG. 1 is a schematic flow chart of a screening method according to an embodiment of the present invention;

fig. 2 is a schematic structural diagram of a screening system according to an embodiment of the present invention.

Detailed Description

Referring to fig. 1, fig. 1 is a schematic flow chart of a screening method provided in an embodiment of the present invention, where the screening method includes the following steps:

step 1), acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database; the disease biological expression database comprises normalized enrichment score values for different pathways of the disease in different models;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database; the drug efficacy database comprises standardized enrichment score values of different pathways of a single drug to different models;

and 2) determining first pathway reversal data of a first model of the target disease and related pathways of the target drug composition, and screening according to the first pathway reversal data to obtain the drug composition.

The invention takes traditional Chinese medicines as an example, and further introduces a screening method of the pharmaceutical composition. It will be appreciated by those skilled in the art that in addition to traditional Chinese medicines, any single drug, including natural products and the like, may be suitable for use in the screening methods described herein. Meanwhile, as can be understood by those skilled in the art, the traditional Chinese medicine includes not only the traditional Chinese medicine itself, but also traditional Chinese medicine extracts and the like, which also fall within the scope of the traditional Chinese medicine described in the present application.

The invention further introduces a screening method of the pharmaceutical composition by taking a cell line model as an example. It will be appreciated by those skilled in the art that in addition to cell line models, animal models, such as mouse models, and the like, and their corresponding metabolic pathways, may also be suitable for use in the screening methods described herein.

The invention establishes a disease biological expression database and a drug efficacy database in advance, wherein the disease biological expression database comprises standardized enrichment scores of diseases in different paths of different cell line models, and the drug efficacy database comprises standardized enrichment score values of different paths of different cell line models by using single traditional Chinese medicine.

The disease may be caused by various metabolic pathway abnormalities, for example, amino acid metabolic pathway, sugar metabolic pathway, fatty acid metabolic pathway abnormalities are all related to the onset of diabetes, and cardiac muscle contraction metabolic pathway, TGF-beta signal pathway, central nerve ligand and receptor interaction pathway, lipid metabolic pathway abnormalities are related to the onset of heart failure. The method combines the existing research results of target diseases or different diseases on different cell line models and different metabolic pathways, classifies the existing research results, and obtains the Normalized Enrichment Score (NES) value of the target diseases or different diseases on different pathways of different cell line models. In this embodiment, the NES value is used to measure the change of each metabolic pathway in the disease, wherein a positive NES value indicates an up-regulation of the metabolic level, a negative NES value indicates a down-regulation of the metabolic level, and the size of the NES value indicates the degree of influence. In one embodiment, the biological manifestation of a disease is described by a disease information matrix whose key information includes metabolic pathway names and NES values. In one embodiment, the key information for the biological manifestation of the disease further includes the name of the disease cell line model.

In one embodiment, the drug efficacy database comprises normalized enrichment score values for different metabolic pathways of different cell line models for a single traditional Chinese medicine. The drug effect database can classify and arrange the existing research results to obtain the standardized enrichment score values of the single traditional Chinese medicine in different metabolic pathways of different cell line models.

The drug effect database can also be established by self, and can be established according to the following method:

carrying out in-vitro experiments on a single traditional Chinese medicine, treating different cell lines by using all single traditional Chinese medicines or candidate single traditional Chinese medicines to respectively obtain cell line gene expression profiles before and after treatment, and carrying out differential gene analysis and gene enrichment analysis on the cell line gene expression profiles before and after treatment to obtain standardized enrichment scoring values (NES values) of the single traditional Chinese medicines in different metabolic pathways of different cell line models. The medicine effect of a single traditional Chinese medicine is expressed by the NES value, the NES value is positive and indicates that the metabolic level is up-regulated, the metabolic pathway is activated, the NES value is negative and indicates that the metabolic level is down-regulated, the metabolic pathway is inhibited, and the NES value indicates the degree of influence. In one embodiment, the effect of a single herb is described by a Chinese herb efficacy matrix, and the key information includes the name of the metabolic pathway and the NES value. In one embodiment, the key information of the efficacy of a single herb also includes the name of the cell line model.

After the target disease is determined, a first cell line model of the target disease and a normalized enrichment score value of a relevant metabolic pathway of the first cell line model are obtained in a pre-established disease biological expression database. In one embodiment, the first cell line model of the target disease is the cell line most correlated with the target disease, e.g., the cell line with the greatest absolute value of normalized enrichment score and its associated metabolic pathways.

And acquiring a target Chinese herbal compound, and then acquiring the standardized enrichment score values of each single drug in the target Chinese herbal compound on the first model and related passages thereof from a drug efficacy database. In the present application, the target chinese herbal compound may be a predetermined chinese herbal compound, or a chinese herbal compound obtained according to a predetermined rule.

In one embodiment, the target chinese herbal compound may be a chinese herbal compound obtained according to a predetermined rule, and the specific process is as follows:

according to the standardized enrichment score values of the target diseases in different channels of the first cell line model, all the single traditional Chinese medicines with the corresponding standardized enrichment score values are obtained from a medicine efficacy database, and the single traditional Chinese medicines are arranged and combined according to a predetermined rule to obtain a traditional Chinese medicine compound.

For example, the selection of the chinese herbal compound is performed based on the disease information matrix including the metabolic pathway name and the NES value and the single drug efficacy matrix including the metabolic pathway name and the NES value, specifically:

aligning the target disease information matrix and the traditional Chinese medicine effect matrix according to the access name, and multiplying the NES value corresponding to the traditional Chinese medicine effect matrix and the disease information matrix to obtain a plurality of traditional Chinese medicine compounds based on the first cell line.

In this embodiment, the combination method adopted when combining the individual Chinese medicinal herbs is an exhaustion method (stand _ CMPD method). In practical application, the drugs may be sorted before being combined, and the sorting rule may be that the drugs are arranged in the order of effective values of the traditional Chinese drugs or in the reverse order.

In practical application, the calculation formula of the effective value Dnes of the medicine such as traditional Chinese medicine is as follows:

wherein p represents a total of p signal paths, DPnes_iRepresenting NES conversion value, DPnes, of the Chinese medicine on the ith metabolic pathway_iThe calculation method comprises the following steps:

DPnes_i＝-sgn(Snes_i*Pnes_i)*Snes_i

wherein, Snes_iRepresents NES value, Pnes of single Chinese medicine on ith metabolic pathway_iThe NES value of the target disease on the ith dysregulated pathway when Snes_i*Pnes_iWhen < 0, DPnes_iValue and Snes_iEqual and vice versa DPnes_iValue of Snes_iThe opposite number of (c).

In another implementation of the present invention, when combining the drugs, the number of the compatible drugs, for example, 6, is preset, that is, when combining the initial drug combinations, each initial drug combination includes 6 different drugs.

Further, the method provided by the application further comprises a pre-established drug annotation information database, wherein the drug annotation information database comprises information such as names, codes (ID), prices, toxicity and the like of single drugs, and drug query is facilitated. In exhaustion, if the combined medicines are traditional Chinese medicines, the combination of the traditional Chinese medicines which are incompatible with each other cannot appear in the formula by combining the database of the traditional Chinese medicines which are incompatible with each other. Besides the contrary mutual incompatibility data, other formula screening and filtering indexes for guiding the formula, such as toxicity, price and the like, belong to the protection scope of the scheme.

After the standardized enrichment score values of the target Chinese herbal compound and each single Chinese herbal medicine in the target Chinese herbal compound on the first cell line model and relevant pathways thereof are obtained, the first pathway reversal data of the target pharmaceutical composition on the first cell line model of the target disease and relevant metabolic pathways thereof are determined, and the Chinese herbal compound is obtained by screening according to the first pathway reversal data.

In one embodiment, the path inversion rate is calculated according to formula (I):

P_reverse＝N_reverse/N_totalformula (I);

in the formula (I), P_reverseIndicates the path inversion rate, N_reverseRepresenting the number of reversal pathways, N, of the pharmaceutical composition in the corresponding model_totalRepresenting the number of pathways associated with the corresponding model and the target disease;

said N is_reverseCalculated according to formula (II) and formula (III):

in formula (II) and formula (III), i represents the ith pathway of the corresponding model, p represents the p pathways shared by the disease of interest on the corresponding model, NES_herbRepresents the normalized enrichment score, NES, of the pharmaceutical composition to be evaluated on the ith pathway_diseaseRepresents a normalized enrichment score value for the disease of interest on the ith pathway;

the NES_herbCalculated according to formula (V):

in the formula (V), m represents m single medicines in the medicinal composition, j represents the jth single medicine in the medicinal composition, Snes_jiIndicating the normalized enrichment score for the jth single drug on the ith pathway.

In the application, the channel reversion rate is the ratio of the number of channels for reversing target diseases in a cell line by the traditional Chinese medicine compound and the number of channels related to the diseases. The channel inversion rate ranges from 0 to 1, wherein the condition that the channel inversion rate is equal to 0 indicates that the Chinese herbal compound has no effect on diseases, and the condition that the channel inversion rate is greater than 0 indicates that the Chinese herbal compound possibly has treatment effect on diseases.

The skilled person can determine the first-pass reversal rate threshold value according to the needs of other classical famous prescriptions, best prescriptions or clinical patients, and screen the Chinese herbal compound according to the threshold value. For example, one skilled in the art can determine that a first-pass reversal rate of 70% or more is considered that a herbal compound may have a therapeutic effect on a disease, and screen a plurality of herbal compounds that satisfy the above threshold.

In the embodiment, the method adopts a parallel processing mode to carry out the drug effect evaluation prediction calculation on the target Chinese herbal compound, divides the whole Chinese herbal compound evaluation calculation task into a series of subtasks, and realizes the high-efficiency Chinese herbal compound evaluation through parallel calculation. The specific parallel computing implementation method is as follows, if m processes are started, the 0 th process is a main process and is responsible for the management work of the queue, and the other m-1 processes are computing processes and are responsible for compound computing evaluation. The main process and the computing process exchange data through interprocess communication, and when the length of the queue is 0, the main process returns a termination signal every time the main process receives a task completion signal.

After the traditional Chinese medicine compound is obtained by screening according to the first cell line model of the target disease, the application also comprises the step of selecting a second cell line model and related passages thereof for verification, and the method specifically comprises the following steps:

obtaining a second cell line model of the target disease and a standardized enrichment score value of a relevant metabolic pathway of the second cell line model from a pre-established disease biological expression database;

acquiring the standardized enrichment score values of each single drug in the screened traditional Chinese medicine compound on the second model and related passages thereof from a pre-established drug efficacy database;

determining second channel reversal data of the traditional Chinese medicine compound obtained by screening according to the first cell line model on a second cell line model of the target disease and relevant metabolic channels of the traditional Chinese medicine compound, and screening according to the second channel reversal data to obtain a plurality of traditional Chinese medicine compounds.

As mentioned above, the same disease may correspond to a plurality of cell line models and a plurality of metabolic pathways, the first cell line with the strongest correlation with the target disease is selected as a screening cell line, and the cell line model with a certain correlation with the target disease or different treatments of the same kind of cells of the first cell line are selected as a second cell line model for verification, so that the accuracy of the obtained traditional Chinese medicine compound is further improved. In the present application, the first cell line model and the second cell line model are independent of each other and correspond to different disease information matrices, respectively.

After the standardized enrichment score values of the second cell line model of the target disease and the relevant metabolic pathways of the second cell line model of the target disease and the standardized enrichment score values of the single traditional Chinese medicines to the second model and the relevant pathways of the second model are obtained, second pathway reversal data of the traditional Chinese medicine compound on the second cell line model of the target disease and the relevant metabolic pathways of the second cell line model of the target disease are determined according to the same method as the method, and a plurality of traditional Chinese medicine compounds are obtained through screening according to the second pathway reversal data. For example, the second path inversion data is the second path inversion rate, and the second path inversion rate is calculated according to the method described above, which is not described herein again.

In addition, the association between the first cell line and the second cell line is made using drug ID or drug chinese name, and when the drug ID is provided by the first cell line in the presence of the corresponding drug in the second cell line, the drug ID is used directly. If the second cell line does not have the drug effect information, searching the Chinese name corresponding to the drug ID in the Chinese drug annotation information database.

Those skilled in the art can determine the second-path inversion rate threshold value according to the requirement, and screen the Chinese herbal compound according to the threshold value. For example, one skilled in the art can determine that a compound Chinese medicinal composition with a second-pass reversal rate of 50% or more may have a therapeutic effect on a disease, and screen a plurality of compound Chinese medicinal compositions that satisfy the above threshold.

If the second cell line model is adopted for verification, the second channel inversion rate calculated by any Chinese herbal medicine compound shows no effect on diseases, or shows that the Chinese herbal medicine compounds possibly effective on the diseases are few, the threshold value of the second channel inversion rate can be reduced, for example, the reduction value of the second channel inversion rate is more than 30%, namely the Chinese herbal medicine compound can be regarded as having possible treatment effect on the diseases.

If the second path inversion rate is reduced, the second path inversion rates obtained by calculating no Chinese herbal compound are all shown to have no effect on diseases, or the number of Chinese herbal compounds possibly effective on diseases is shown to be less, the first path inversion rate threshold value can be reduced, namely the range of the Chinese herbal compounds in the first screening is expanded, and the verification is carried out according to the method the same as the method.

In one embodiment of the present invention, the method further comprises selecting a third cell line model and its associated pathways for validation, specifically comprising:

acquiring a third cell line model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring the standardized enrichment score values of each single drug in the traditional Chinese medicine compound on the third model and related passages thereof, which are obtained by the first verification, from a pre-established drug efficacy database;

determining third channel reversal data of a third model of the traditional Chinese medicine compound on the target disease and related channels thereof obtained by screening according to the second cell line model, and screening according to the third channel reversal data to obtain the pharmaceutical composition.

As described above, the same disease may correspond to multiple cell line models and multiple metabolic pathways, and the present application selects the first cell line with the strongest correlation with the target disease as the screening cell line, and simultaneously selects one or more cell line models with a certain correlation with the target disease or different treatments of the same cell of the first cell line as the second cell line model, the third cell line model, or even the nth cell line model for verification, thereby further improving the accuracy of the obtained traditional Chinese medicine compound. In the present application, the first cell line model, the second cell line model, the third cell line model and even the nth cell line model are independent of each other and correspond to different disease information matrices, respectively.

After the normalized enrichment score values of the third cell line model of the target disease and the relevant metabolic pathways of the third cell line model of the target disease and the normalized enrichment score values of each single traditional Chinese medicine to the third model and the relevant pathways of the third cell line model are obtained, the third cell line model of the target disease and the third pathway reversal data of the traditional Chinese medicine compound obtained by screening according to the second cell line model are determined according to the same method as the method, and a plurality of traditional Chinese medicine compounds are obtained by screening according to the third pathway reversal data. For example, the third path inversion data is the third path inversion rate, and the third path inversion rate is calculated according to the method described above, which is not described herein again.

Similarly, the association between the third cell line and the second cell line is made using the drug ID or drug chinese name, and the drug ID is used directly when the second cell line provides the drug ID with the corresponding drug present in the third cell line. If the third cell line does not have the medicine effect information, searching the Chinese name corresponding to the medicine ID in the Chinese medicine annotation information database.

And when a plurality of verification cell line models are selected, the traditional Chinese medicine compound obtained by the previous cell line verification is circularly used for continuing verification until the verification work of all cell membrane models is completed.

The skilled person in the art can determine the inversion rate threshold of the third path and the nth path as required, and screen the Chinese herbal compound according to the threshold. For example, one skilled in the art can determine that a compound Chinese medicinal composition with a second channel reversal rate of 30% or more may have a therapeutic effect on a disease, and screen a plurality of compound Chinese medicinal compositions that satisfy the above threshold.

If the third cell line model is adopted for verification, the third-path inversion rate calculated by any Chinese herbal medicine compound shows no effect on diseases, or shows that the Chinese herbal medicine compounds possibly effective on the diseases are fewer, and the threshold value of the third-path inversion rate can be reduced, for example, the third-path inversion rate is reduced by more than 10%, so that the Chinese herbal medicine compound can be considered to have possible treatment effect on the diseases.

If the third path inversion rate is reduced, the third path inversion rate obtained by calculating no Chinese herbal medicine compound is still displayed to have no effect on diseases, or the Chinese herbal medicine compound possibly effective on the diseases is displayed to be less, the second path inversion rate threshold value can be reduced, namely the range of the Chinese herbal medicine compound in the first verification is expanded, and the verification is carried out according to the method the same as the method.

In addition to the rate of reversal of the pathway, the number of reversal of the pathway, etc. may also be used as the screening criteria.

In one embodiment, a three-cell-line traditional Chinese medicine compound formula is performed for heart failure diseases. First, IPS-CM cells were selected as the master cell line, and HCF and HK2 cells as the slave cell lines. Depending on the biological manifestations of the disease, the IPS-CM cell line finally selected 26 pathways associated with heart failure disease, and the HCF and HK2 cell lines selected 24 and 32 pathways, respectively. Then, the medicine effect NES value of the traditional Chinese medicine on the target pathway is obtained through in vitro cell experiments and biological information analysis. And finally, carrying out a traditional Chinese medicine compound formula, and obtaining 12 multi-cell line traditional Chinese medicine compounds under the condition that 90% of target pathways are reversed in a main cell line IPS-CM and 75% of target pathways are reversed by accessory cell lines HCF and HK2, wherein the results are shown in table 1, and table 1 is the result of the compound formula of the heart failure cell line.

TABLE 1 Heart failure three-cell line compound formula results

The reversal rate of pathway and the effective rate of drug "; "separate" and represent the passage reversal rate of the above Chinese herbal compound in IPS-CM, HCF and HK2 cell lines, respectively.

In another embodiment, two-cell line herbal compound is performed for lung cancer, and first, RPMI2650 cells are selected as the primary cell line and THP1 cells are selected as the secondary cell line. Based on the biological manifestations of the disease, 27 pathways associated with lung cancer were selected in the RPMI2650 cell line and 21 pathways were selected in the THP1 cell line. Then, the efficacy NES value of the candidate traditional Chinese medicine on the target pathway is obtained through cell experiments and biological information analysis, and finally, the traditional Chinese medicine compound formula evaluation is carried out, and 9 multi-cell-line traditional Chinese medicine compounds are obtained by taking the main cell line RPMI2650 with 90% of the target pathway reversed and the accessory cell line THP1 with 85% of the target pathway reversed as a threshold value, and the results are shown in table 2, and the table 2 is the lung cancer two-cell-line compound formula result.

TABLE 2 Compound recipe results for two cell lines of lung cancer

The reversal rate of pathway and the effective rate of drug "; "separate, respectively, as in RPMI 2650; channel reversal rates in THP1 cell line.

The screening method of the pharmaceutical composition provided by the invention comprises the following steps of firstly, obtaining a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database; then obtaining the standardized enrichment score values of the target drug composition and each single drug in the target drug composition on the first model and relevant pathways of the first model; and finally, determining first channel reversal data of a first model of the target disease and related channels of the target drug composition, and screening according to the first channel reversal data to obtain the drug composition. The method provided by the invention utilizes the relevant knowledge of biomedicine and in-vitro experimental data, and carries out the combination evaluation of a large number of candidate single medicaments and the creation of new medicaments of the medicinal composition on the basis of the influence of the single medicament on the gene expression of different models, does not need to carry out basic research on a large number of Chinese medicinal components, and has lower cost and more accurate result.

Furthermore, the method provided by the invention is verified by combining 2 or more than 2 types of model gene expression profile data, and has high reliability and strong repeatability.

Referring to fig. 2, fig. 2 is a schematic structural diagram of a screening system according to an embodiment of the present invention, where the screening system includes: a first target disease information acquisition module 11, a target drug acquisition module 12 and a first analysis and screening module 13.

The screening system provided by the application comprises a first target disease information acquisition module 11, which is used for acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database.

The screening system provided by the application comprises a target drug acquisition module 12, wherein the target drug acquisition module 12 is used for acquiring a target drug composition and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database.

In one embodiment, the target drug obtaining module 12 includes a drug composition obtaining module for obtaining a target drug composition and a drug efficacy information obtaining module for obtaining a normalized enriched score value of each single drug in the target drug composition for the first model and its associated pathways.

The screening system provided by the application comprises a first analysis screening module 13, wherein the first analysis screening module is used for determining first passage reversal data of a first model of a target disease and related passages of the target disease of a target pharmaceutical composition, and screening the target pharmaceutical composition according to the first passage reversal data to obtain the pharmaceutical composition.

In one embodiment, the first analysis and screening module 13 includes a first analysis module and a first screening module, wherein the first analysis module is configured to calculate first pathway reversal data of the target pharmaceutical composition for the first model of the target disease and its associated pathways according to the method described above, and the first screening module screens the chinese herbal compound according to the preset first pathway reversal data.

In one embodiment, the screening system provided herein further comprises:

a second target disease information acquisition module 14, configured to acquire a second model of a target disease and a normalized enrichment score value of a relevant pathway thereof from a pre-established disease biological expression database;

a second drug information acquisition module 15, configured to acquire, from a pre-established drug efficacy database, a normalized enrichment score value of each single drug in the drug composition obtained by the first analysis and screening module on the second model and its related pathways;

and the second analysis and screening module 16 is used for determining second channel reversal data of the second model of the target disease and the related channels of the pharmaceutical composition screened by the first analysis and screening module, and screening the pharmaceutical composition according to the second channel reversal data.

In one embodiment, the second analysis and screening module 16 includes a second analysis module and a second screening module, wherein the second analysis module is configured to calculate the second pathway reversal data of the second model of the target disease and the related pathways of the target pharmaceutical composition according to the method described above, and the second screening module screens the chinese herbal compound according to the preset second pathway reversal data threshold.

In one embodiment, the second analysis and screening module 16 further includes a third screening module, and the third screening module is configured to change a preset second channel reversal data threshold according to the chinese herbal compound screened by the second screening module, and screen the chinese herbal compound according to the changed second channel reversal data threshold.

In one embodiment, the screening system provided herein further comprises:

a third target disease information acquisition module 17, configured to acquire a third model of a target disease and a normalized enrichment score value of a relevant pathway thereof from a pre-established disease biological expression database;

a third drug information acquisition module 18, configured to acquire, from a pre-established drug efficacy database, a normalized enrichment score value of each single drug in the drug composition obtained by the second analysis and screening module on the third model and its related pathways;

and the third analysis and screening module 19 is used for determining third channel reversal data of the third model of the target disease and the related channels of the pharmaceutical composition obtained by screening of the second analysis and screening module, and screening the pharmaceutical composition according to the third channel reversal data.

In one embodiment, the third year analysis and screening module 19 includes a third analysis module and a fourth screening module, wherein the third analysis module is configured to calculate third channel reversal data of the target pharmaceutical composition for the third model of the target disease and its associated channels according to the method described above, and the fourth screening module screens the chinese herbal compound according to a preset third channel reversal data threshold.

In one embodiment, the third analyzing and screening module 19 further includes a fifth screening module, and the fifth screening module is configured to change a preset third path reversal data threshold according to the chinese herbal compound screened by the fourth screening module, and screen the chinese herbal compound according to the changed third path reversal data threshold.

Correspondingly, the embodiment of the invention also provides electronic equipment for screening the pharmaceutical composition, which comprises a memory and a processor;

wherein the memory is used for storing programs;

the processor calls a program and is used to:

acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database;

determining first pathway reversal data of a first model of the target medicine composition on the target disease and relevant pathways of the target disease, and screening according to the first pathway reversal data to obtain the medicine composition.

The screening system of the pharmaceutical composition provided by the invention utilizes relevant knowledge of biomedicine and in-vitro experimental data, and performs combination evaluation of a large number of candidate single drugs and new drug creation of the pharmaceutical composition based on the influence of the single drug on gene expression of different models, does not need basic research of traditional Chinese medicine components, and has lower cost and more accurate result. The screening system of the pharmaceutical composition can be used for research and development and creation of new compound traditional Chinese medicines, combines the influence of single traditional Chinese medicines on gene expression in different cell line models, utilizes cross validation of a plurality of cell line models, and goes deep into the action size and action direction of the compound traditional Chinese medicines in different paths to realize prediction of new compound traditional Chinese medicines, and lays a foundation for research and development points of new compound traditional Chinese medicines.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (10)

1. A method of screening for a pharmaceutical composition comprising the steps of:

step 1), acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database; the disease biological expression database comprises normalized enrichment score values for different pathways of the disease in different models;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database; the drug efficacy database comprises standardized enrichment score values of different pathways of a single drug to different models;

and 2) determining first pathway reversal data of a first model of the target disease and related pathways of the target drug composition, and screening according to the first pathway reversal data to obtain the drug composition.

2. The screening method of claim 1, further comprising:

step 3), acquiring a second model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

obtaining the standardized enrichment score values of each single drug in the pharmaceutical composition determined in the step 2) on the second model and the related passages thereof from a pre-established drug efficacy database;

and 4) determining second channel reversal data of the second model of the target disease and the related channels of the pharmaceutical composition screened in the step 2), and screening according to the second channel reversal data to obtain the pharmaceutical composition.

3. The screening method according to claim 2, further comprising:

step 5), acquiring a third model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring the normalized enrichment score values of each single drug in the pharmaceutical composition determined in the step 4) on the third model and the related passages thereof from a pre-established drug efficacy database;

and 6) determining third channel reversal data of the third model of the target disease and the related channels of the pharmaceutical composition screened in the step 4), and screening according to the third channel reversal data to obtain the pharmaceutical composition.

4. The screening method of claim 3, wherein the first model is a first cell line model, the second model is a second cell line model, and the third model is a third cell line model;

or, the first model is a first animal model, the second model is a second animal model, and the third model is a third animal model.

5. The screening method according to claim 3, wherein the first lane reversal data is a first lane reversal rate, the second lane reversal data is a second lane reversal rate, and the third lane reversal data is a third lane reversal rate;

or the first channel reversal data is a first channel reversal number, the second channel reversal data is a second channel reversal number, and the third channel reversal data is a third channel reversal number.

6. The screening method according to claim 5, wherein the pathway reversal rate is calculated according to formula (I):

P_reverse＝N_reverse/N_totalformula (I);

in the formula (I), P_reverseIndicates the path inversion rate, N_reverseRepresenting the number of reversal pathways, N, of the pharmaceutical composition in the corresponding model_totalRepresenting the number of pathways associated with the corresponding model and the target disease;

said N is_reverseCalculated according to formula (II) and formula (III):

in the formulae (II) and (III), i represents the ith pathway of the corresponding model, and p represents the target disease on the corresponding modelTotal p pathways, NES_herbRepresents the normalized enrichment score, NES, of the pharmaceutical composition to be evaluated on the ith pathway_diseaseRepresents a normalized enrichment score value for the disease of interest on the ith pathway;

the NES_herbCalculated according to formula (V):

in the formula (V), m represents m single medicines in the medicinal composition, j represents the jth single medicine in the medicinal composition, Snes_jiIndicating the normalized enrichment score for the jth single drug on the ith pathway.

7. The screening method according to any one of claims 1 to 6, wherein the single drug is a single Chinese medicine or a single Chinese medicine extract; the pharmaceutical composition is a Chinese herbal compound.

8. A system for screening pharmaceutical compositions, comprising:

the first target disease information acquisition module is used for acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

the target drug acquisition module is used for acquiring a target drug composition and acquiring the standardized enrichment score values of each single drug in the target drug composition on the first model and the relevant passages thereof from a pre-established drug efficacy database;

the first analysis and screening module is used for determining first passage reversal data of a first model of the target disease and related passages of the target drug composition, and screening the target drug composition according to the first passage reversal data to obtain the drug composition.

9. The screening system of claim 8, further comprising:

the second target disease information acquisition module is used for acquiring a second model of the target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

the second drug information acquisition module is used for acquiring the standardized enrichment score values of each single drug in the drug composition obtained by the first analysis and screening module on the second model and the related passages from a pre-established drug efficacy database;

and the second analysis and screening module is used for determining second channel reversal data of the second model of the target disease and the related channel of the pharmaceutical composition screened by the first analysis and screening module, and screening the pharmaceutical composition according to the second channel reversal data.

10. An electronic device for pharmaceutical composition screening, comprising a memory and a processor;

wherein the memory is used for storing programs;

the processor calls a program and is used to:

acquiring a first model of a target disease and a standardized enrichment score value of a relevant passage thereof from a pre-established disease biological expression database;

acquiring a target drug composition, and acquiring a standardized enrichment score value of each single drug in the target drug composition on a first model and a relevant passage thereof from a pre-established drug efficacy database;

determining first pathway reversal data of a first model of the target medicine composition on the target disease and relevant pathways of the target disease, and screening according to the first pathway reversal data to obtain the medicine composition.

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