KR20150098998A - Method of testing the safety for drug garget membrane protein - Google Patents

Abstract

The present invention relates to a method of testing safety for a drug target membrane protein comprising: a step (a) of setting relation between the target protein for each drugs and a phenomenon caused by drug side effects on the basis of the testing drug, information on side effect occurrence thereof, and information about the target protein corresponding to the testing drug; a step (b) of deducing information on the gene rewiring rate by analyzing properties of the target proteins for each drugs; and a step (c) of selecting the target protein which is the target of the testing drug based on the relation between the target protein for each drugs and the phenomenon caused by drug side effect on the basis of information on the gene rewiring rate.

Description

TECHNICAL FIELD The present invention relates to a method for testing a drug target membrane protein,

The present invention relates to a method for testing the safety of a drug target protein, and more particularly, to a method for testing the safety of a drug target protein by analyzing the characteristics of a target protein targeted by the drug (hereinafter referred to as a target protein) To a method for testing the safety of a target protein.

Developing a new drug that is safe from side effects can be the first step in reducing the time and cost of developing a new drug from selecting a target protein that is safe from the risk of drug side effects.

Biopolymers such as proteins, peptides, and RNAs function by binding to target substances in vivo. In particular, since the basic units of these bonds are mediated by protein bonds, the identification of other proteins that bind to a particular protein is used as an indicator of the functional relevance of these proteins. Thus, the identification of a particular protein by binding to unknown binding proteins and demonstrating a specific function and its association with a drug provides a direct opportunity to determine a new drug target as well as to study cell signaling mechanisms, It can provide the base technology for discovering new drug candidates in the delivery system.

Thus, the target protein may be directly affected by the drug and cause unintended consequences, so it is necessary to have clear information as to which features of the target protein are responsible for activating the unexpected function in the drug.

Drug side effects are the unintended effects of drug-targeted proteins on the cell system, so the severity of drug side effects depends on which target protein is selected. Modulation of a therapeutic target targeted by a chemical will modulate the biological system, where unintended consequences of modulation lead to drug side effects. More than 30% of the drugs developed by investing a lot of development time and time are actually being withdrawn because of various unexpected side effects in clinical trials.

However, to date, no technology has been developed to explain the safety of a target modulated in a biological system, and no technology has been developed to diagnose the severity of drug side effects based on the target protein. Thus, understanding the modulation of target proteins in a biological system may be key to solving drug side effects.

SUMMARY OF THE INVENTION It is an object of the present invention to solve the above-mentioned problems, and it is an object of the present invention to provide a pharmaceutical composition for treating a drug, To provide a safety indicator for the vehicle.

It is also an object of the present invention to propose a dynamic network analysis technique of a target protein based on the intracellular localization of a target protein and a large capacity network analysis technique using a high performance cluster.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, unless further departing from the spirit and scope of the invention as defined by the appended claims. It will be possible.

A method for testing safety of a membrane protein to be a drug target according to one embodiment of the present invention for solving the above-mentioned problems comprises the steps of: (a) detecting occurrence of side effects of the test drug and the drug, Establishing a linkage between the drug-specific target protein and the drug side effect phenomenon based on the target protein information corresponding to the target protein; (b) deriving gene rewiring rate information by analyzing protein property information on the drug-specific target protein; And (c) selecting a target protein to be a target of the drug to be tested based on the relationship between the drug-specific target protein and the drug adverse effect phenomenon based on the gene reconstitution ratio information.

According to an embodiment of the present invention, the step (a) may include deriving side effect occurrence information of the drug to be tested and the drug based on the drug information DB storing information on occurrence of side effects occurring for a plurality of drugs and each drug ; And deriving the target protein information corresponding to the test subject drug and the drug based on the drug-protein information DB storing the target protein information corresponding to the plurality of drugs and the respective drugs.

Advantageously, the drug information DB is an integrated drug that converts a plurality of drug information annotated in various terms collected from one or more drug information DB into UMLS (Unified Medical Language System) An information DB can be used.

The step (b) according to an embodiment of the present invention may include the step of selecting the gene reconstitution ratio information as a stability index for the target protein of the test subject drug.

According to an embodiment of the present invention, the step (c) further comprises: performing a protein subcellular localization of a cellular dynamic network and a protein on the basis of the gene reconstitution ratio information; And selecting a target protein to be a target of the drug to be tested based on the relationship between the cell dynamic network and the result of predicting the intracellular location of the protein, and the relationship between the drug-specific target protein and the drug adverse effect phenomenon.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the present invention by those skilled in the art. And can be understood and understood.

According to the embodiment of the present invention, the side effect of the drug is an unintended influence of the protein targeted by the drug to the body, so that the side effect of the drug can provide a safety index of the target protein crystal to the target protein for safe new drug development .

Also, according to embodiments of the present invention, it is possible to provide a dynamic network analysis technique of a target protein based on the intracellular localization of a target protein and a large capacity network analysis technique using a high performance cluster.

In addition, according to the embodiment of the present invention, selection of a safe target protein in the screening step of the drug development process can reduce the time and cost for developing a new drug.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of the specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing an example of a target protein test result related to an embodiment of the present invention. FIG.
Figure 2 is a plot of test results regarding the association between the target centrality of a target protein and drug side effects in connection with an embodiment of the present invention.
FIG. 3 is a diagram showing an example of the rate at which a signal transduction path is reconstructed according to the organization of a protein-protein interaction network related to an embodiment of the present invention.
FIG. 4 shows an example of a graph showing a correlation between the protein reconstitution rate and the number of drug side effects in relation to the example of the present invention.
FIG. 5 is an example for analyzing a correlation between a drug remodeling rate and a gene rearrangement ratio of a membrane protein according to an embodiment of the present invention.
FIG. 6 is another embodiment for analyzing the correlation between the drug remodeling rate and the gene rearrangement ratio of the membrane protein according to the embodiment of the present invention.
7 is a flowchart illustrating a drug safety test procedure according to an embodiment of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention is capable of various modifications and various embodiments, and specific embodiments are illustrated in the drawings and described in detail in the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.

Hereinafter, preferred embodiments according to the present invention will be described in detail with reference to the accompanying drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following detailed description, together with the accompanying drawings, is intended to illustrate exemplary embodiments of the invention and is not intended to represent the only embodiments in which the invention may be practiced. The following detailed description includes specific details in order to provide a thorough understanding of the present invention. However, those skilled in the art will appreciate that the present invention may be practiced without these specific details.

A side effect of a drug is that when a target protein targeted by a drug (hereinafter, referred to as a 'target protein') becomes a hub for signal transmission on the intercellular network in a biological system constituting a human body, Thereby causing a number of drug side effects. Protein-Protein Interaction (PPI) is a protein-protein interaction (PPI) that increases as the centrality of the target protein increases. ) The influence of modulation on the network is increased, and the possibility of drug side effects is increased more.

However, there is no explanation for the adverse drug reactions that occur in non-hub proteins to determine whether a target protein is merely an afferent indicator of the protein.

The present invention relates to a method for testing the safety of a target protein (hereinafter, referred to as "target protein") as a method for minimizing adverse drug effects, and more specifically, And the relationship between the target protein and the side effects of the target protein.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing an example of a target protein test result related to an embodiment of the present invention. FIG.

The graph shown in FIG. 1 shows a result of a protein test according to a drug. The graph shows a resolution of a membrane target and a soluble target for each of a plurality of drug groups classified according to drug risk, (Number of side effects).

Drug groups are divided into multiple groups according to the drug risk. In the examples of the present invention, a first group consisting of functional drugs (nutraceuticals) such as vitamins, approved drugs A group of drugs can be grouped into two groups and a third group consisting of withdrawn drugs that are not approved beyond the predefined safety baseline.

At this time, the target protein can be classified into a membrane protein (A) and a soluble protein (B) according to the annotation of cell structure of the gene ontology.

Referring to Figure 1, the drug test results illustrated in Figure 1 (a) show that membrane protein (A) and water soluble protein (B), when administered to the first to third groups of drugs, 1 (b) shows the number of side effects (number of occurrences) that can be induced through the membrane protein (A) and the water-soluble protein (B) upon drug administration of the first group to the third group side effects.

Referring to FIG. 1 (a), it can be seen that the degree of cleavage increases as the drug of a group with a higher risk increases, and that the degree of cleavage increases as the degree of cleavage increases. have. In the case of the membrane protein, the protein protein degradation degree is about 20% in the drug group 1, the protein degradation degree in the drug group 2 is about 40%, and the protein degradation degree in the drug group 3 is about 60% The higher the risk, the greater the degree of degradation.

On the other hand, in the case of the water-soluble protein (B), the degree of fragmentation becomes smaller as a group of drugs having a higher risk is added. That is, an increase in the degree of cleavage of the membrane protein in the high-risk drug group means that the membrane protein designated as the drug target has a fatal weakness in functioning as the target.

Next, referring to FIG. 1 (b), it can be seen that the number of cases in which side effects are caused by drugs having a high risk is increased with increasing drug risks both in the membrane protein (A) and in the water soluble protein (B) . Among them, the membrane protein (A) has a higher number of side effects than the water-soluble protein (B) on the average, so that the membrane protein (A) .

Figure 2 is a plot of test results regarding the association between the target centrality of a target protein and drug side effects in connection with an embodiment of the present invention.

Referring to FIG. 2, similarly, the target protein is classified into a membrane protein and a water-soluble protein, and a relationship between the target center point and the number of side effects is shown graphically when the drug is administered to the membrane protein and the water-soluble protein.

FIG. 2 (a) is a graph showing the number of adverse reactions according to the target degree of the total protein including the membrane protein and the water-soluble protein. FIG. 2 (b) And FIG. 2 (c) is a graph showing the number of adverse effects with respect to the frequency of the membrane protein.

In Figures 2 (a) to 2 (c), the number of side effects of each drug is shown as an average value of values corresponding to each bin divided by 2 for the target protein (total protein, membrane protein and water-soluble protein) , And frequency of 18 or more without a frequency of 20, the number of side effects of each protein was shown by the frequency of each protein so that 50 target proteins were included in each bin. The number of side effects of each drug is an average value obtained by detecting the number of side effects in each of total protein, membrane protein and water soluble protein contained in each bin.

FIG. 2 (d) is a graph showing the frequency of drug side effects in frequency in the target protein, and FIG. 2 (e) is a graph showing the rate of cell death as one of adverse drug reactions in the target protein. f) is a graph showing the proportion of drug withdrawn from the target protein.

FIG. 2 (d) to FIG. 2 (f) show that the membrane protein is sensitive to the drug and the number of side effects is higher than that of the water-soluble protein. Specifically, referring to FIG. 2 (d), it can be seen that the number of side effects of the drug increases in the frequency of the membrane protein in comparison with that of the water-soluble protein. Referring to FIG. 2 (e) 2 (f), it can be seen that the membrane protein is much more abolished than the water-soluble protein due to the side effects of the drug test.

Thus, referring to the test results illustrated in FIG. 2, it can be seen that the membrane protein has a higher frequency of drug side effects than the water-soluble protein, and thus the response to the risk of the input drug is high.

Membrane proteins can be used as an indicator of drug risk in that they have many functions to transmit cell signals through the periphery of the cell, although they do not show many interactions at the same time due to environmental and spatial restrictions due to the membrane structure. Therefore, in order to allow the membrane protein to function well as a primary gate in an intracellular signal transduction system upon drug injection, the present invention provides a method for setting a drug safety test index so as to specifically interact with the state or tissue of a membrane protein present.

FIG. 3 is a diagram showing an example of the rate at which a signal transduction path is reconstructed according to the organization of a protein-protein interaction network related to an embodiment of the present invention.

Referring to FIG. 3, diversity information of a cell signal network is derived based on tissue-specific expression data and interaction network information between protein-protein, and information of a drug test target protein The relationship between the risk of adverse drug reactions can be analyzed.

Specifically, FIG. 3 (a) shows an example of an integrated protein-protein interaction, and shows an example in which a comprehensive protein-protein interaction network is constructed by integrating a plurality of inter-activity databases. The exemplified protein Interactum 310 shows an integrated network with 10,229 protein nodes and 108,508 interactions. Among the tens of thousands of proteins constituting the protein interac- term 310, protein A (311) and protein B (312) can be identified to analyze gene expression patterns.

FIG. 3 (b) shows a gene expression map in a PPI network for a specific protein (A, B) from a protein interactam as a gene expression map. By mapping a tissue-specific gene expression profile to integrated protein interaction information A tissue-specific interaction network can be constructed.

3 (b) shows the gene expression pattern between the specific protein A and the partner with respect to the protein A 311 as a tissue-protein matrix type map 320, and the right side shows the protein B (312) (330) in the form of a tissue-protein matrix.

For example, the white boxes 321 and 331 indicate that the proteins of the tissues are not expressed, and the color boxes 322 and 332 ) Indicates that the protein of the tissue is expressed.

Analysis of the information represented by each map reveals that the tissue-specific gene expression type information from the map 320 of the protein A includes a first type 323 in which all genes are expressed, a second type 324 in which genes at specific positions are not expressed ), A third form (325) in which genes at other positions are not expressed, and the like. Similarly, various forms (333, 334, 335) can be reconstructed according to the position and the number of the gene from the map (330) of the protein B.

At this time, the gene rewiring rate can be specified as one of the indexes for measuring the protein network activity. Comparing the results of gene expression pattern reconstruction of protein A and protein B, protein A has a lower genetic reconstruction rate than protein B and establishes a static network, while protein B has a higher gene rearrangement ratio than protein A, As shown in Fig. That is, the higher the rate of gene rearrangement, the more dynamic the cell network and the more specific the tissue interaction, while the lower the gene rearrangement rate, the more stable the cell network and the more basic interactions.

The correlation between the protein rearrangement ratio and the number of adverse drug reactions is also related to the network dynamic characteristics of the protein. This will be described below with reference to FIG.

FIG. 4 shows an example of a graph showing a correlation between the protein reconstitution rate and the number of drug side effects in relation to the example of the present invention.

4 (a) to 4 (c) are graphs showing the correlation between the ratio of gene rearrangement to the total target protein, the water-soluble protein, and the membrane protein, respectively, and the number of adverse drug reactions. In each graph, bin is configured to contain 100 target proteins in each bin in ascending order based on the gene rearrangement ratio, and the number of adverse drug reactions represented by each bin is the number of drug side effects It represents the average value of the number of times.

Figure 4 (a) shows the correlation between the number of adverse drug reactions and the rate of gene rearrangement for the entire target protein mixed with the membrane protein and the water-soluble protein. As the ratio of gene rearrangement increases, Can be confirmed. The reason for this is as follows. In the case of the water-soluble protein shown in FIG. 4 (b), the proportional tendency between the gene rearrangement ratio and the number of drug side effects is not large, whereas in the case of the membrane protein shown in FIG. 4 (c) Considering the high proportional tendency of the number of occurrences, the rate of gene recombination inherent in membrane protein can be set as an index of risk for drug side effects by selecting membrane protein as a target adverse drug target.

FIG. 5 is an example for analyzing a correlation between a drug remodeling rate and a gene rearrangement ratio of a membrane protein according to an embodiment of the present invention.

In membrane proteins, which are more affected by drug risks than water-soluble proteins, the risk of the same drug varies depending on the ratio of gene rearrangement.

5 (a), the number of adverse drug reactions (501) in the membrane protein having a gene rearrangement ratio of 80% or more (501) is significantly higher than the number of adverse drug reactions (502) in the membrane protein having a gene rearrangement ratio of 20% Can be confirmed.

5B, the degree of cell death (503) of a membrane protein having a gene rearrangement ratio of 80% or more is also 1.5 times as high as that of a membrane protein having a gene rearrangement ratio of 20% or less (504) 5 (c), the withdrawal rate (505) of a drug targeted for a membrane protein having a gene rearrangement ratio of 80% or more is also shown in the case of withdrawing a drug targeting a membrane protein having a gene rearrangement ratio of 20% or less Is increased by about 3 times as compared with the case of FIG.

From these results, it can be seen that the membrane protein having a high network dynamic characteristic is greatly influenced by the drug risk compared to the membrane protein having a low network dynamic characteristic.

FIG. 6 is another embodiment for analyzing the correlation between the drug remodeling rate and the gene rearrangement ratio of the membrane protein according to the embodiment of the present invention.

In membrane proteins, which are more affected by drug risks than water-soluble proteins, the degree of gene rearrangement can be used to determine how sensitive is the detection of cell death as part of drug side effects.

Referring to FIG. 6, a drug test for a membrane protein with a gene rearrangement ratio of 80 percent resulted in a false positive rate of 18.3 percent for measuring cell death, whereas a membrane protein with a gene rearrangement ratio of 90 percent As a result of the drug test, the false positive rate for the cell death test is 6.2%. As the gene rearrangement rate is higher, the cell death is included in the side effect of the drug, so that the detection accuracy of the drug side effect is enhanced.

Therefore, according to the embodiment of the present invention, the rate of gene rearrangement of a membrane protein to be a target of a drug can be set as an early predictor of the severity of adverse drug reactions. In the top 20 percent of the gene rearrangement ratios, more than 50 percent of the target proteins have drug side effects including cell death, and the top 15 percent of the gene rearrangement ratios include drug retraction target proteins.

7 is a flowchart illustrating a drug safety test procedure according to an embodiment of the present invention.

Referring to FIG. 7, the drug safety test process according to an embodiment of the present invention includes a drug information DB storing a plurality of drugs and side effect occurrence information that is generated for each drug, Information is derived (S701).

At this time, the drug information DB includes an integrated drug information DB for converting and annotating a plurality of drug information annotated in various terms collected from one or more drug information DB into UMLS (Unified Medical Language System) codes and storing the drug information DB . Alternatively, a method of deriving necessary drug information from one or more established drug information databases may be used.

In step S702, drug information to be tested and target protein information corresponding to the drug are derived based on the drug-protein information DB storing information on target proteins (membrane proteins) corresponding to a plurality of drugs and respective drugs.

Drug information and drug side effect occurrence information derived on the basis of each information DB and target protein information corresponding to drug information are mapped and the relationship between the drug side effect phenomenon that occurs in the drug stability test in a target protein for a specific drug (S703).

For the purpose of comprehensive drug side-effect analysis, the relationship between the drug and the target protein is determined by the drug stability test, the association between the approved drug and the target protein, the relationship between the target drug and the target protein, A relationship between target adverse drug-target proteins including at least one of association among target proteins can be established.

Next, the target protein derived from the drug-protein information database is analyzed for protein property information that can provide a direct basis for the occurrence of adverse drug reaction (S704).

As a result of the analysis of the protein property information, the gene rewiring rate information is derived (S705). Gene reconstitution rate takes into account the environmental and functional properties of membrane proteins, so that many membrane proteins are not placed in the same environment and exhibit dynamic interaction behavior as much as they have to respond to specific conditions. In other words, the gene rearrangement ratio can be regarded as a characteristic associated with the dynamics of the cell network of the membrane protein.

Based on the derived gene rearrangement ratio information as a drug safety index, stable membrane proteins are selected for the drug through protein cellular subcellular localization of the cellular dynamic network and protein based on the index (S706) The drug stability test is performed using the membrane protein (S707).

In this way, selection of stable target protein at the screening stage of the drug development process, by selecting a stable membrane protein with a high gene reconstruction ratio through prediction of cellular dynamic network and intracellular location of the protein, Can be reduced rapidly.

Thus, the identification of a particular protein by binding to unknown binding proteins and demonstrating a specific function and its association with a drug provides a direct opportunity to determine a new drug target as well as to study cell signaling mechanisms, It can provide the base technology for discovering new drug candidates in the delivery system.

The foregoing description is merely illustrative of the technical idea of the present invention, and various changes and modifications may be made by those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments of the present invention are not intended to limit the scope of the present invention but to limit the scope of the present invention. The scope of protection of the present invention should be construed according to the following claims, and all technical ideas within the scope of equivalents thereof should be construed as being included in the scope of the present invention.

Claims (5)

A method for testing the safety of a membrane protein to be a drug target,
(a) establishing a relationship between a drug to be tested and a drug side effect phenomenon based on side effects of the drug under test and target protein information corresponding to the drug under test;
(b) deriving gene rewiring rate information by analyzing protein property information on the drug-specific target protein; And
(c) selecting a target protein to be a target of the drug to be tested based on the relationship between the drug-specific target protein and the drug side effect phenomenon based on the gene recombination ratio information, . The method according to claim 1,
The step (a)
Deriving side effect occurrence information of the test subject drug and the corresponding drug based on a drug information DB storing a plurality of drugs and side effect occurrence information appearing for each drug; And
Obtaining a target drug information corresponding to the test subject drug and the drug based on the drug-protein information DB storing a plurality of drugs and target protein information corresponding to each drug, Methods for testing the safety of proteins. 3. The method of claim 2,
The drug information DB comprises:
A drug target database that uses an integrated drug information DB that converts a plurality of drug information annotated in various terms collected from one or more drug information databases into UMLS (Unified Medical Language System) Methods for testing the safety of proteins. The method according to claim 1,
The step (b)
And selecting the gene rearrangement ratio information as a stability index for the target protein of the test subject drug. The method according to claim 1,
The step (c)
Performing protein subcellular localization of a cellular dynamic network and a protein based on the gene reconstitution ratio information; And
Selecting a target protein to be a target of the drug to be tested on the basis of a relationship between the cell dynamic network and a result of predicting the intracellular location of the protein and the relationship between the target protein and the drug adverse effect phenomenon, A method for testing the safety of membrane proteins.

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