Combined drug generation method, system and storage medium based on transcriptome map

Abstract

The present invention provides a method, system and storage medium for generating a combination drug based on a transcriptome map. The method includes the steps of: obtaining a plurality of abnormal pathways related to the regulation of a target disease; screening out a plurality of drug small molecules that have a reverse regulatory effect on the abnormal pathways according to the transcript map characteristics of the drug small molecules; respectively calculating the overall reverse regulatory effect of each of the drug small molecules relative to each of the abnormal pathways to obtain the reverse regulation score of each of the drug small molecules relative to the target disease; and combining each of the drug small molecules according to the reverse regulation score to obtain a combination drug. The present invention can obtain a combination drug capable of performing combined regulation for complex diseases and complex biological processes to improve the regulation effect.

Description

Technical Field

[0001] The present invention relates to the field of medical technologies, and particularly to a method, a system and a storage medium for generating combination drugs based on a transcriptome map. Background Art

[0002] The transcriptome refers to the sum of all RNAs that can be transcribed in a cell or a group of cells under the same environment (or physiological conditions). In recent years, the rise of transcriptomics technology has provided new ideas for the discovery of disease marker genes and drug targets. For example, by performing differential analysis on the transcriptome sequencing results of specific disease tissue samples and normal tissues, it is possible to know which genes are differentially expressed (up-regulated or down-regulated) in the disease; by performing differential analysis on the transcriptome sequencing results of drug small molecule interference cell lines and normal cell lines, it is possible to know which genes' expressions can be intervened and regulated (promoted or inhibited) by the drug small molecules.

[0003] Currently, the new drug discovery ideas based on transcriptomics have been extended from many angles. For example, based on the gene expression profile, key genes determining the disease are discovered as potential drug action targets, and then potential active small molecules with regulatory effects are screened according to the drug interference transcriptome (focusing on a few genes); or according to whether there is an obvious negative correlation between the expression profile characteristics of the disease and the interference expression profile characteristics of the drug small molecules (focusing on the genes of the system), etc.

[0004] However, the existing ideas and methods all focus on the gene level, while the occurrence and abnormalities of diseases are often the result of abnormal perturbations of several normal biological processes in the human body, rather than the result of the regulation of several genes alone. Therefore, a method for generating combination drugs that can perform combined regulation on complex diseases and complex biological processes is needed. Summary of the Invention

[0005] The present invention provides a method, a system and a storage medium for generating combination drugs based on a transcriptome map, which can achieve the complementary combination of pathways by regulating the disease-causing pathways and achieve the effect of treating complex diseases. The specific technical solutions are as follows:

[0006] The present invention provides a method for generating combination drugs based on a transcriptome map, including the steps of:

[0007] Obtaining a plurality of abnormal pathways related to the regulation of a target disease;

[0008] According to the transcriptome map characteristics of drug small molecules, screening out a plurality of drug small molecules having a reverse regulatory effect on the abnormal pathways;

[0009] Calculate the overall reverse regulatory effect of each of the drug small molecules relative to each of the abnormal pathways, and obtain the reverse regulation score of each of the drug small molecules relative to the target disease;

[0010] Combine each of the drug small molecules according to the reverse regulation score to obtain a combined drug.

[0011] The method for generating a combined drug based on a transcriptome map provided by the present invention screens out a number of drug small molecules related to disease regulation, and combines the drug small molecules according to the reverse regulation score of each drug small molecule relative to the disease, so as to calculate drug small molecules with potential activity for disease regulation based on transcriptome data, and quickly calculate the effect of a combined drug for a complex disease with disease pathways as characteristics.

[0012] In some embodiments, the obtaining a number of abnormal pathways related to the regulation of a target disease specifically includes:

[0013] Obtain a number of significantly differentially expressed genes of the target disease;

[0014] Perform enrichment analysis on the significantly differentially expressed genes to obtain a first preset number of regulatory pathways with the highest relevance to the target disease as the abnormal pathways;

[0015] After obtaining the number of abnormal pathways related to the regulation of the target disease and before screening out a number of drug small molecules having a reverse regulatory effect on the abnormal pathways, it further includes:

[0016] Mark the differential expression direction and degree of each of the significantly differentially expressed genes on the abnormal pathways.

[0017] The method for generating a combined drug based on a transcriptome map provided by the present invention discloses a method of performing enrichment analysis on significantly differentially expressed genes of a target disease and using a number of regulatory pathways with the highest disease relevance as abnormal pathways. While meeting the accuracy of abnormal pathway identification, only the pathways with relatively high relevance are retained, achieving a balance between analysis speed and analysis accuracy. At the same time, the differential expression direction and degree of significantly differentially expressed genes on the abnormal pathways are marked, facilitating subsequent combination of drug molecules.

[0018] In some embodiments, the obtaining a number of significantly differentially expressed genes of the target disease specifically includes:

[0019] Perform transcriptome sequencing on the target disease through a gene expression omnibus database;

[0020] Compare the transcriptome sequencing results of the diseased tissue of the target disease with the transcriptome sequencing results of the normal tissue to obtain disease differentially expressed genes;

[0021] Screen the disease differentially expressed genes according to the degree of difference and the significance of the difference, and obtain the second preset number of the significantly different genes.

[0022] The method for generating a combination drug based on a transcriptome map provided by the present invention identifies disease differentially expressed genes according to the transcriptome sequencing results of diseased tissues and normal tissues, and screens the disease differentially expressed genes according to the degree of difference and the significance of the difference to obtain significantly different genes, while improving the relevance between the significantly different genes and the disease causative factors, reducing the computational amount of the abnormal pathways identified according to the significantly different genes subsequently, and improving the efficiency of combining drug molecules.

[0023] In some embodiments, the obtaining of a plurality of abnormal pathways related to the regulation of a target disease specifically includes:

[0024] Obtain the associated genes of the target disease through a preset database;

[0025] Locate the associated genes in regulatory pathways, and use the regulatory pathways containing at least one of the associated genes as the abnormal pathways, and the associated genes on the abnormal pathways as significantly different genes;

[0026] After obtaining the plurality of abnormal pathways related to the regulation of the target disease and before screening out a plurality of drug small molecules having a reverse regulatory effect on the abnormal pathways, it further includes:

[0027] Count the number of up-regulated and down-regulated expressions of the plurality of significantly different genes included in each of the abnormal pathways respectively, and use the gene direction with the largest number as the differential expression direction of the corresponding abnormal pathway.

[0028] The method for generating a combination drug based on a transcriptome map provided by the present invention, after identifying the associated genes of the disease through a database, uses the regulatory pathways including the associated genes as abnormal pathways, and determines the expression direction of the abnormal pathways according to the expression directions of the associated genes in the abnormal pathways, further improving the rate of identifying the abnormal pathways and their expression directions.

[0029] In some embodiments, the calculating of the overall reverse regulatory effect of each of the drug small molecules relative to each of the abnormal pathways specifically includes:

[0030] Obtain the differential expression directions of the respective significantly different genes included in each of the abnormal pathways;

[0031] According to the interfering transcriptome characteristics of each of the drug small molecules, obtain the overall reverse regulatory effect of each of the drug small molecules relative to each of the abnormal pathways.

[0032] The method for generating a combination drug based on a transcriptome map provided by the present invention calculates the overall reverse regulatory effect of a small drug molecule relative to each abnormal pathway based on the differential expression direction, and comprehensively considers the influence of the small drug molecule on the abnormal channels of the disease.

[0033] In some embodiments, obtaining the reverse regulation score of each of the small drug molecules relative to the target disease specifically includes:

[0034] Taking the enrichment degree of each of the abnormal pathways in the target disease as the weight of the abnormal pathway;

[0035] According to the weight of each of the abnormal pathways and the overall reverse regulatory effect corresponding to each of the abnormal pathways, obtaining the reverse regulation score of each of the small drug molecules relative to the target disease.

[0036] The method for generating a combination drug based on a transcriptome map provided by the present invention further discloses a method for calculating the reverse regulation score of a small drug molecule on a target disease according to the enrichment degree of an abnormal pathway in the target disease and the overall reverse regulatory effect corresponding to the abnormal pathway, improving the calculation efficiency and calculation accuracy of the reverse regulation score of the small drug molecule relative to the target disease.

[0037] In some embodiments, after obtaining the reverse regulation score of each of the small drug molecules relative to the target disease and before combining each of the small drug molecules according to the reverse regulation score, it further includes:

[0038] Performing a secondary screening on the small drug molecules according to whether the up-regulated gene set of the target disease is significantly enriched in the inhibitory expression gene set of the small drug molecule and whether the down-regulated gene set of the target disease is significantly enriched in the promoting expression gene set of the small drug molecule.

[0039] The method for generating a combination drug based on a transcriptome map provided by the present invention performs a secondary screening on the small drug molecules by whether the up-regulated gene set and the down-regulated gene set of the target disease are significantly enriched in the expression gene set of the small drug molecule, further improving the accuracy of the drug combination.

[0040] In one embodiment, combining each of the small drug molecules according to the reverse regulation score to obtain a combination drug specifically includes:

[0041] Sorting the small drug molecules according to the reverse regulation score;

[0042] Selecting several of the small drug molecules with the highest reverse regulation scores for combination to obtain an initial combination drug;

[0043] Perform further screening of the small molecule drugs for the abnormal pathways that cannot be reversely regulated by the initial combination drug until the combination drug is obtained.

[0044] The method for generating a combination drug based on a transcriptome map provided by the present invention discloses a method of first selecting small molecule drugs with the highest reverse regulation score for combination, and then performing further screening and combination of small molecule drugs according to the abnormal pathways that cannot be reversely regulated by the preliminary combination drug, comprehensively considering the influence of small molecule drugs on abnormal pathways, and enhancing the effect of the combination drug.

[0045] In some embodiments, the present invention further provides a system for generating a combination drug based on a transcriptome map, including:

[0046] An acquisition module, configured to acquire a plurality of abnormal pathways related to the regulation of a target disease;

[0047] A screening module, connected to the acquisition module, configured to screen out a plurality of small molecule drugs having a reverse regulation effect on the abnormal pathways according to the transcriptome map characteristics of the small molecule drugs;

[0048] A calculation module, connected to the screening module, configured to calculate the overall reverse regulation effect of each small molecule drug relative to each abnormal pathway, and obtain the reverse regulation score of each small molecule drug relative to the target disease;

[0049] A combination module, configured to combine each small molecule drug according to the reverse regulation score to obtain a combination drug.

[0050] In some embodiments, the present invention further provides a storage medium, in which at least one instruction is stored, and the instruction is loaded and executed by a processor to implement the operations performed by the above-mentioned method for generating a combination drug based on a transcriptome map.

[0051] The present invention provides a method, a system and a storage medium for generating a combination drug based on a transcriptome map, and at least includes the following technical effects:

[0052] (1) Realize the calculation of small molecule drugs with potential activity for disease regulation based on transcriptome data, and quickly calculate the effect of combination drugs for complex diseases with disease pathways as characteristics;

[0053] (2) By performing enrichment analysis on the significantly different genes of the target disease, and using the several regulatory pathways with the highest disease relevance as abnormal pathways, while meeting the accuracy of abnormal pathway recognition, only retain the pathways with relatively large relevance;

[0054] (3) Identify disease differentially expressed genes based on the transcriptome sequencing results of diseased tissues and normal tissues, and screen the disease differentially expressed genes according to the degree of difference and significance of difference to obtain significantly differentially expressed genes, which can improve the relevance between the significantly differentially expressed genes and disease causes while reducing the computational workload of abnormal pathways identified based on the significantly differentially expressed genes later, and improve the efficiency of combining drug molecules;

[0055] (4) Use the regulatory pathways including associated genes as abnormal pathways, and determine the expression direction of each abnormal pathway according to the expression direction of the associated genes in the abnormal pathway, which can further improve the rate of identifying abnormal pathways and their expression directions;

[0056] (5) Calculate the reverse regulation score of drug small molecules against the target disease by according to the enrichment degree of the abnormal pathway in the target disease and the overall reverse regulation effect corresponding to the abnormal pathway, which can improve the computational efficiency and accuracy of calculating the reverse regulation score of drug small molecules relative to the target disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The following will further illustrate the above characteristics, technical features, advantages and their implementation manners of the present solution in a clear and easy-to-understand manner in combination with the drawings.

[0058] Figure 1 is a flowchart of a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0059] Figure 2 is a flowchart of obtaining abnormal pathways of a target disease in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0060] Figure 3 is another flowchart of obtaining abnormal pathways of a target disease in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0061] Figure 4 is a flowchart of calculating the reverse regulation score of drug small molecules relative to a target disease in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0062] Figure 5 is an example diagram of the scoring and screening results of drug small molecules for 10 abnormal regulation pathways selected for a specific disease in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0063] Figure 6 is an example diagram of the scoring of the drug small molecule with the highest reverse regulation degree for each pathway and the drug small molecule with the highest overall reverse regulation degree in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0064] Figure 7 It is another flowchart of a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0065] Figure 8 It is an example diagram of the reverse regulation scoring of a drug compound prescription generated by a method for generating combination drugs based on a transcriptome map provided by the present invention for abnormal pathways of a disease;

[0066] Figure 9 It is a specific distribution schematic diagram of a drug small molecule regulating genes and abnormal genes of a disease-related pathway in a method for generating combination drugs based on a transcriptome map provided by the present invention;

[0067] Figure 10 It is an example diagram of the reverse regulation relationship between a drug compound prescription generated by a method for generating combination drugs based on a transcriptome map provided by the present invention and significantly abnormal regulatory pathways of a disease;

[0068] Figure 11 It is an example diagram of a system for generating combination drugs based on a transcriptome map provided by the present invention.

[0069] Reference numerals in the figure: acquisition module - 10, screening module - 20, calculation module - 30, and combination module - 40. Detailed implementation manners

[0070] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the specific implementation manners of the present invention will be described below with reference to the accompanying drawings. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings, and other implementation manners can be obtained.

[0071] To make the drawings concise, only the parts related to the present invention are schematically shown in each drawing, and they do not represent the actual structure of the product. In addition, to make the drawings concise and easy to understand, in some drawings, components with the same structure or function are only schematically shown for one of them, or only one of them is marked. In this document, "one" not only means "only this one", but also means "more than one" situation.

[0072] This application discloses a solution for identifying differentially expressed genes in diseased tissues based on transcriptomics and generating combination drugs by combining drug small molecules. The specific differential expression analysis and drug combination solution are as follows:

[0073] First, obtain a number of abnormal pathways related to the regulation of the target disease. Then, according to the transcriptional atlas characteristics of small molecule drugs, screen out small molecule drugs that have a reverse regulatory effect on the abnormal regulatory pathways of the disease. According to the reverse regulation scores of each small molecule drug on the target disease, select 1-2 small molecule compounds with the strongest reverse regulatory effect on all the abnormal pathways of the target disease. Then, for the pathways that cannot be regulated by this compound, screen out small molecule compounds with significant regulatory effects, and combine the two small molecule compounds to form a drug compound prescription to achieve a comprehensive reverse regulation of the disease.

[0074] Among them, this application provides three schemes for obtaining a number of abnormal pathways related to the regulation of the target disease. The first scheme is to discover the abnormal regulatory pathways of the disease through the transcriptional sequencing analysis of the disease based on the Gene Expression Omnibus (GEO) database, and perform differential analysis on the transcriptional sequencing results of the diseased tissue and the normal tissue to obtain significant disease differentially expressed genes. According to the degree of difference (Log2FoldChange) and the significance of difference (P<0.01), the top 300 significant differentially expressed genes of the disease are screened out. Enrichment analysis is performed on these genes against the Biological Process (BP) entry database of the Gene Ontology (GO) to screen out n pathways most relevant to the disease, such as n = 10, and further mark the differential expression direction and degree of the disease differential genes in these n pathways.

[0075] The second scheme is to identify disease-associated genes and regulatory pathways based on the Online Mendelian Inheritance in Man (OMIM) database. For the target disease, collect genes related to the target disease through data collation. If a pathway has at least 1 coincidence of disease differential genes and is based on the hypergeometric distribution or Fisher's exact test (P<0.01), this pathway will be selected as an abnormal disease regulatory pathway. When there are n such pathways, such as n = 10, the differential expression direction and degree of this regulatory pathway are jointly determined by the expression directions and expression significance levels of all its disease differential genes. The joint determination is specifically manifested as counting the number of up-regulated and down-regulated genes, and the direction of the genes with the larger number is the direction of the regulatory pathway change.

[0076] The third solution is to identify associated genes and regulatory pathways based on a literature annotation database. For a target disease, disease-associated genes are collected through literature annotation databases, including online databases such as GeneCards, DisGeNet, and GeneGO. The discovery of these genes focuses on the processes involved in disease occurrence. The processes of identifying and counting the regulatory pathways, the differential expression directions, and degrees of the regulatory pathways are the same as those in the steps of the second solution.

[0077] After identifying the abnormal pathways, the differential expression directions, and degrees of the abnormal pathways of the target disease through any one of the above three solutions, according to the transcriptional map characteristics of small molecule drugs, small molecule drugs that can produce a reverse regulatory effect on the disease abnormal regulatory pathway are screened. For example, for the abnormal pathway A enriched by disease differential genes, among the 100 genes that make up pathway A, according to the expression map characteristics of the disease, 30 genes are significantly highly expressed, 40 genes are significantly lowly expressed, and 30 genes have no regulatory effect; for the interfering transcriptome characteristics of drug X, for pathway A and the characteristic expression of the disease, among the 30 highly expressed genes of the disease, 20 of them have an inhibitory expression effect; among the 40 lowly expressed genes of the disease, 30 of them have a promoting expression effect. Further calculate the overall reverse regulatory effect of the small molecule drug on the disease abnormal regulatory pathway A, and use the enrichment degree of this pathway in the disease as the weight; calculate the overall reverse regulatory effects of the other 9 pathways in turn, and finally calculate the reverse regulatory score (Reverse Regulated Score, RRS) of the small molecule drug for this disease.

[0078] Identify whether the up-regulated gene set of the disease is significantly enriched in the inhibitory expression gene set of the small molecule drug; whether the down-regulated gene set of the disease is significantly enriched and analyzed in the promoting expression gene set of the small molecule drug. Combining the two-way enrichment results of the disease up- and down-regulated gene sets in the interfering transcriptome map of the small molecule drug, further screen active small molecules, so that the screening results are more credible.

[0079] After screening out small molecule drugs whose reverse regulatory scores for the target disease meet the expected values in the above solutions, first select 1-2 small molecule drug compounds with the strongest overall reverse regulatory effect on the disease abnormal pathways. For the pathways that cannot be regulated by this compound, screen for drug compounds with significant regulatory effects on this part of the pathways again, so that the final formed drug compound prescription has a comprehensive reverse regulatory effect on the disease.

[0080] In one embodiment, after performing differential analysis on the transcriptome sequencing results of diseased tissues and normal tissues to obtain significant disease differentially expressed genes, the top 300 significant differentially expressed genes of the disease are selected according to the degree of difference (Log2FoldChange) and the significance of the difference (P<0.01). These genes are subjected to enrichment analysis on the biological process entry database from Gene Ontology. According to the screening conditions showing that the enriched p.adj is less than 0.01, the min Geneset size is 100, and the channel redundancy correction is less than 0.6, n pathways most relevant to the disease are selected, such as n = 10, and the differential expression directions and degrees of the disease differential genes in these n pathways are further marked. Taking each pathway as a unit, the abnormal regulation of the disease on this pathway is evaluated, and further the reverse regulation degree of traditional Chinese medicine (TCM) on the abnormal regulation of traditional Chinese medicine is evaluated, and a comprehensive score is calculated with the pathway enrichment degree as the weight. The scoring criteria are as follows:

[0081] ;

[0082] Calculate the overall reverse regulation effects of the other 9 pathways in turn, and finally calculate the reverse regulation score of the drug small molecules on the disease. Based on the above scoring, several combinations of drug small molecules are selected in order to expect to achieve the full reverse regulation effects on 10 pathways.

[0083] In one embodiment, as Figure 1 shown, the present invention provides a method for generating a combination drug based on a transcriptome map, including the steps of:

[0084] S100 Obtain several abnormal pathways related to the regulation of the target disease.

[0085] S200 According to the transcriptome map characteristics of the drug small molecules, screen out several drug small molecules having a reverse regulation effect on the abnormal pathways.

[0086] S300 Calculate the overall reverse regulation effects of each drug small molecule relative to each abnormal pathway respectively, and obtain the reverse regulation scores of each drug small molecule relative to the target disease.

[0087] S400 Combine each drug small molecule according to the reverse regulation scores to obtain a combination drug.

[0088] The method for generating a combination drug based on a transcriptome map provided by this embodiment screens out several drug small molecules related to disease regulation, and combines the drug small molecules according to the reverse regulation scores of each drug small molecule relative to the disease, realizes the calculation of drug small molecules with potential activity on disease regulation based on transcriptome data, and quickly calculates the effects of combination drugs for complex diseases with disease pathways as characteristics.

[0089] In one embodiment, as Figure 2 shown, step S100 obtains a number of abnormal pathways related to the regulation of the target disease, specifically including:

[0090] S111 obtains a number of significantly differentially expressed genes of the target disease.

[0091] Specifically, transcriptome sequencing of the target disease is performed through the Gene Expression Omnibus database. The transcriptome sequencing results of the diseased tissue of the target disease are compared with those of the normal tissue to obtain disease differentially expressed genes, and the disease differentially expressed genes are screened according to the degree of difference and significance of difference to obtain a second preset number of significantly differentially expressed genes.

[0092] S112 performs enrichment analysis on the significantly differentially expressed genes to obtain a first preset number of regulatory pathways with the highest relevance to the target disease as abnormal pathways.

[0093] Before step S100 obtains a number of abnormal pathways related to the regulation of the target disease and step S200 screens out a number of small molecule drugs with a reverse regulatory effect on the abnormal pathways according to the transcriptomic map characteristics of the small molecule drugs, it further includes:

[0094] S113 marks the differential expression direction and degree of each significantly differentially expressed gene on the abnormal pathway.

[0095] Specifically, in this embodiment, the disease abnormal regulatory pathway is discovered based on the disease transcriptome sequencing analysis of the Gene Expression Omnibus (GEO) database, and significant disease differentially expressed genes are obtained by performing differential analysis on the transcriptome sequencing results of the diseased tissue and the normal tissue. According to the degree of difference (Log2FoldChange) and significance of difference (P<0.01), the top 300 significantly differentially expressed genes of the disease are screened out. These genes are subjected to enrichment analysis on the Biological Process (BP) entry database of Gene Ontology (GO) to screen out n pathways most relevant to the disease, such as n = 10, and further mark the differential expression direction and degree of the differential genes of the disease in these n pathways.

[0096] During the enrichment analysis process, according to the screening conditions of showing an enrichment p.adj less than 0.01, a min Geneset size of 100, and a channel redundancy correction less than 0.6, the pathways related to the disease are screened out.

[0097] This embodiment discloses a method of enriching and analyzing significantly different genes for a target disease, and taking several regulatory pathways with the highest disease relevance as abnormal pathways. While meeting the accuracy of abnormal pathway recognition, only the pathways with relatively large correlations are retained, achieving a balance between analysis speed and analysis accuracy. At the same time, the differential expression directions and degrees of significantly different genes on the abnormal pathways are marked, facilitating subsequent combination of drug molecules.

[0098] In one embodiment, as Figure 3 shown, step S100 of obtaining several abnormal pathways related to the regulation of the target disease specifically includes:

[0099] S121 Obtain the associated genes of the target disease through a preset database.

[0100] S122 Locate the associated genes on the regulatory pathways, and take the regulatory pathways containing at least one associated gene as abnormal pathways, and the associated genes on the abnormal pathways as significantly different genes.

[0101] Before step S100 of obtaining several abnormal pathways related to the regulation of the target disease and step S200 of screening several drug small molecules with reverse regulatory effects on the abnormal pathways according to the transcriptional map characteristics of the drug small molecules, it further includes:

[0102] S123 respectively count the number of up-regulated and down-regulated expressions of several significantly different genes included in each abnormal pathway, and take the gene direction with the largest number as the differential expression direction of the corresponding abnormal pathway.

[0103] Specifically, in this embodiment, disease-associated genes and regulatory pathways can be identified based on the Online Mendelian Inheritance in Man (OMIM) database. For the target disease, genes related to the target disease are collected through data collation. If a pathway has at least 1 overlap of disease-differential genes and is based on the hypergeometric distribution or Fisher's exact test (P < 0.01), this pathway will be selected as the disease-regulation abnormal pathway. When there are n pathways, such as n = 10, the differential expression direction and degree of this regulatory pathway are jointly determined by the expression directions and significant degrees of all its disease-differential genes. The joint determination is specifically manifested as counting the number of up-regulated and down-regulated genes, and the gene direction with the largest number is the regulatory pathway change direction.

[0104] In this embodiment, associated genes and regulatory pathways can also be identified based on a literature annotation database. For a target disease, through a literature annotation database, including online databases such as GeneCards, DisGeNet, and GeneGO, disease-associated genes are collected. The discovery of these genes focuses on the processes involved in disease occurrence. The process of identifying and statistically analyzing their regulatory pathways, the differential expression directions and degrees of the regulatory pathways is the same as the steps in the solution for identifying disease-associated genes and regulatory pathways based on the Online Mendelian Inheritance in Man (OMIM) database.

[0105] After identifying the disease-associated genes through a database in the method for generating a combined drug based on a transcriptome map provided in this embodiment, the regulatory pathways including the associated genes are used as abnormal pathways, and the expression direction of each abnormal pathway is determined by the expression direction of the associated genes in the abnormal pathway, further improving the rate of identifying abnormal pathways and their expression directions.

[0106] In some embodiments, as Figures 4 - 6 shown, step S300 calculates the overall reverse regulation effect of each drug small molecule relative to each abnormal pathway, and obtains the reverse regulation score of each drug small molecule relative to the target disease, specifically including:

[0107] S310 obtains the differential expression directions of each significant differential gene included in each abnormal pathway.

[0108] S320 obtains the overall reverse regulation effect of each drug small molecule relative to each abnormal pathway according to the interference transcriptome characteristics of each drug small molecule.

[0109] S330 takes the enrichment degree of each abnormal pathway in the target disease as the weight of the abnormal pathway.

[0110] S340 obtains the reverse regulation score of each drug small molecule relative to the target disease according to the weight of each abnormal pathway and the overall reverse regulation effect corresponding to each abnormal pathway.

[0111] Specifically, as Figure 5 shown, Figure 5 is an example diagram of the scoring and screening results of drug small molecules for 10 abnormal regulatory pathways selected for a specific disease. Among them, for the constituent genes of each specific pathway, according to the directions of disease abnormality and drug interference, they can be divided into three categories. The higher the trans index, the more significant the reverse regulation effect. Mark the differential expression directions and degrees of the differential genes of the disease in n pathways. Taking each pathway as a unit, evaluate the abnormal regulation of the disease on this pathway.

[0112] And further evaluate the reverse regulation degree of traditional Chinese medicine (TCM) on the abnormal regulation of traditional Chinese medicine. The comprehensive scoring is carried out with the pathway enrichment degree as the weight. The scoring criteria are as follows:

[0113] ;

[0114] Calculate the overall reverse regulatory effects of the other 9 pathways in sequence, and finally calculate the reverse regulation score of the small molecule drug for this disease.

[0115] As Figure 6 shown, Figure 6 is an example diagram of the scoring of the small molecule drug with the highest reverse regulation degree and the small molecule drug with the highest overall reverse regulation degree for each pathway.

[0116] The method for generating a combination drug based on a transcriptome map provided in this embodiment calculates the overall reverse regulatory effect of a small molecule drug relative to each abnormal pathway based on the differential expression direction, comprehensively considers the influence of the small molecule drug on the abnormal channels of the disease, and further discloses a method for calculating the reverse regulation score of the small molecule drug for the target disease according to the enrichment degree of the abnormal pathway in the target disease and the overall reverse regulatory effect corresponding to the abnormal pathway, improving the calculation efficiency and calculation accuracy of the reverse regulation score of the small molecule drug relative to the target disease.

[0117] In one embodiment, as Figures 7 - 10 shown, the present invention also provides a method for generating a combination drug based on a transcriptome map, including the steps of:

[0118] S100 Obtain a number of abnormal pathways related to the regulation of the target disease.

[0119] S200 According to the transcriptome map characteristics of the small molecule drug, screen out a number of small molecule drugs that have a reverse regulatory effect on the abnormal pathway.

[0120] S300 Calculate the overall reverse regulatory effect of each small molecule drug relative to each abnormal pathway respectively, and obtain the reverse regulation score of each small molecule drug relative to the target disease.

[0121] S350 According to whether the up-regulated gene set of the target disease is significantly enriched in the inhibitory expression gene set of the small molecule drug, and whether the down-regulated gene set of the target disease is significantly enriched in the promoting expression gene set of the small molecule drug, perform secondary screening on the small molecule drug.

[0122] S410 Sort the small molecule drugs according to the reverse regulation score.

[0123] S420 Select a number of small molecule drugs with the highest reverse regulation scores for combination to obtain an initial combination drug.

[0124] S430 Further screen the small molecule drugs for the abnormal pathways that the initial combination drug cannot reverse regulate until a combination drug is obtained.

[0125] Specifically, after screening out small molecule drugs whose reverse regulation scores for the target disease meet the expected values, first select 1-2 small molecule compounds of the drug with the strongest reverse regulation effect on the overall disease abnormal pathway. For the pathways that cannot be regulated by this compound, screen for drug compounds with significant regulatory effects on this part of the pathways again, so that the finally formed drug compound prescription has a comprehensive reverse regulation effect on the disease.

[0126] After obtaining the combined drug, the reverse regulation score of the drug prescription for the disease abnormal pathway can be calculated, and the reverse regulation effects of each small molecule in the drug compound prescription on the significantly abnormal regulatory pathways of the disease can be displayed. For example, Figures 8 to 10 as shown, Figure 8 is an example diagram of the reverse regulation score of the selected drug prescription for the disease abnormal pathway. Figure 9 is a specific distribution diagram of a small molecule drug regulating genes and abnormal genes related to the disease pathway. Figure 10 is an example diagram of the overall reverse regulation effect of the selected drug compound prescription on the significantly abnormal regulatory pathways of the disease.

[0127] In some embodiments, as Figure 11 shown, the present invention further provides a combined drug generation system based on a transcriptome map, including an acquisition module 10, a screening module 20, a calculation module 30, and a combination module 40.

[0128] The acquisition module 10 is used to acquire a number of abnormal pathways related to the regulation of the target disease.

[0129] The screening module 20 is connected to the acquisition module 10 and is used to screen out a number of small molecule drugs with reverse regulation effects on the abnormal pathways according to the transcript map characteristics of the small molecule drugs.

[0130] The calculation module 30 is connected to the screening module 20 and is used to calculate the overall reverse regulation effects of each small molecule drug relative to each abnormal pathway respectively, and obtain the reverse regulation scores of each small molecule drug relative to the target disease.

[0131] The combination module 40 is used to combine each small molecule drug according to the reverse regulation scores to obtain a combined drug.

[0132] The combined drug generation system based on the transcriptome map provided in this embodiment screens out a number of small molecule drugs related to disease regulation, and combines the small molecule drugs according to the reverse regulation scores of each small molecule drug relative to the disease, realizes the calculation of small molecule drugs with potential activity for disease regulation based on transcriptome data, and quickly calculates the effects of combined drugs for complex diseases with disease pathways as characteristics.

[0133] In one embodiment, the present invention further provides a storage medium storing at least one instruction, which is loaded and executed by a processor to implement the operations performed by the above-described embodiment of the method for generating a combination drug based on a transcriptome map. For example, the storage medium may be a read-only memory (ROM), a random access memory (RAM), a compact disc read-only memory (CD-ROM), magnetic tape, floppy disk, and optical data storage device, etc.

[0134] They can be implemented by program codes executable by a computing device. Thus, they can be stored in a storage device for execution by the computing device, or they can be separately fabricated into individual integrated circuit modules, or multiple modules or steps among them can be fabricated into a single integrated circuit module for implementation. In this way, the present invention is not limited to any specific combination of hardware and software.

[0135] It should be noted that the above embodiments can be freely combined as needed. The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for generating a combination drug based on a transcriptome map, characterized in that, Including the steps: Obtain a number of abnormal pathways related to the regulation of the target disease; According to the transcriptional map characteristics of small molecule drugs, screen out a number of small molecule drugs that have a reverse regulatory effect on the abnormal pathways; Calculate the overall reverse regulatory effect of each small molecule drug relative to each abnormal pathway, and obtain the reverse regulatory score of each small molecule drug relative to the target disease; According to the reverse regulatory scores, combine each small molecule drug to obtain a combined drug, specifically including: sorting the small molecule drugs according to the reverse regulatory scores, selecting a number of the small molecule drugs with the highest reverse regulatory scores for combination to obtain an initial combined drug, and further screening the small molecule drugs for the abnormal pathways that cannot be reversely regulated by the initial combined drug until the combined drug is obtained; The obtaining of the reverse regulatory score of each small molecule drug relative to the target disease specifically includes: taking the enrichment degree of each abnormal pathway in the target disease as the weight of the abnormal pathway; according to the weights of each abnormal pathway and the overall reverse regulatory effect corresponding to each abnormal pathway, obtaining the reverse regulatory score of each small molecule drug relative to the target disease; After obtaining the reverse regulatory score of each small molecule drug relative to the target disease and before combining each small molecule drug according to the reverse regulatory score, it further includes: performing a secondary screening on the small molecule drugs according to whether the up-regulated gene set of the target disease is significantly enriched in the inhibitory expression gene set of the small molecule drug and whether the down-regulated gene set of the target disease is significantly enriched in the promoting expression gene set of the small molecule drug.

2. The method for generating a combined drug based on a transcriptome map according to claim 1, wherein, The obtaining of a number of abnormal pathways related to the regulation of the target disease specifically includes: Obtain a number of significantly differentially expressed genes of the target disease; Perform enrichment analysis on the significantly differentially expressed genes to obtain the first preset number of regulatory pathways with the highest relevance to the target disease as the abnormal pathways; After obtaining a number of abnormal pathways related to the regulation of the target disease and before screening out a number of small molecule drugs that have a reverse regulatory effect on the abnormal pathways, it further includes: Mark the differential expression direction and degree of each significantly differentially expressed gene on the abnormal pathway.

3. The method for generating a combined drug based on a transcriptome map according to claim 2, wherein, The obtaining of a number of significantly differentially expressed genes of the target disease specifically includes: Perform transcriptome sequencing on the target disease through the Gene Expression Omnibus database; Compare the transcriptome sequencing results of the diseased tissue of the target disease with the transcriptome sequencing results of the normal tissue to obtain disease differentially expressed genes; Screen the disease differentially expressed genes according to the degree of difference and significance of difference to obtain the second preset number of significantly differentially expressed genes.

4. The method for generating a combination drug based on a transcriptome map according to claim 1, wherein The obtaining of a number of abnormal pathways related to the regulation of the target disease specifically includes: Obtain the associated genes of the target disease through a preset database; Locate the associated gene in a regulatory pathway, and use the regulatory pathway containing at least one of the associated genes as the abnormal pathway, and the associated genes on the abnormal pathway as significantly differentially expressed genes; Before screening out a number of small molecule drugs with a reverse regulatory effect on the abnormal pathway after obtaining a number of abnormal pathways related to the regulation of a target disease, it further includes: Respectively count the number of up-regulated and down-regulated expressions of a number of the significantly differentially expressed genes contained in each of the abnormal pathways, and use the gene direction with the largest number as the differential expression direction of the corresponding abnormal pathway.

5. The method for generating a combined drug based on a transcriptome map according to any one of claims 2 or 4, characterized in that The specific calculation of the overall reverse regulatory effect of each of the small molecule drugs relative to each of the abnormal pathways includes: Obtain the differential expression direction of each of the significantly differentially expressed genes contained in each of the abnormal pathways; According to the interference transcriptome characteristics of each of the small molecule drugs, obtain the overall reverse regulatory effect of each of the small molecule drugs relative to each of the abnormal pathways.

6. A combinatorial drug generation system based on a transcriptome map, characterized in that, It includes: An acquisition module for obtaining a number of abnormal pathways related to the regulation of a target disease; A screening module, connected to the acquisition module, for screening out a number of small molecule drugs with a reverse regulatory effect on the abnormal pathway according to the transcriptional map characteristics of the small molecule drugs; A calculation module, connected to the screening module, for respectively calculating the overall reverse regulatory effect of each of the small molecule drugs relative to each of the abnormal pathways to obtain the reverse regulation score of each of the small molecule drugs relative to the target disease; the specific process of obtaining the reverse regulation score of each of the small molecule drugs relative to the target disease includes: using the enrichment degree of each of the abnormal pathways in the target disease as the weight of the abnormal pathway; according to the weight of each of the abnormal pathways and the overall reverse regulatory effect corresponding to each of the abnormal pathways, obtain the reverse regulation score of each of the small molecule drugs relative to the target disease; A combination module for combining each of the small molecule drugs according to the reverse regulation score to obtain a combined drug, specifically including: sorting the small molecule drugs according to the reverse regulation score, selecting a number of the small molecule drugs with the highest reverse regulation score for combination to obtain an initial combined drug, and further screening the small molecule drugs for the abnormal pathways that cannot be reversely regulated by the initial combined drug until the combined drug is obtained; after obtaining the reverse regulation score of each of the small molecule drugs relative to the target disease and before combining each of the small molecule drugs according to the reverse regulation score, it further includes: performing a secondary screening of the small molecule drugs according to whether the up-regulated gene set of the target disease is significantly enriched in the inhibitory expression gene set of the small molecule drug and whether the down-regulated gene set of the target disease is significantly enriched in the promoting expression gene set of the small molecule drug.

7. A storage medium, characterized in that, At least one instruction is stored in the storage medium, and the instruction is loaded and executed by a processor to implement the operations performed by the method for generating a combination drug based on a transcriptome map according to any one of claims 1-5.

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