CN108268749A - A kind of method for predicting pharmaceuticals toxic effect pattern - Google Patents

Abstract

The invention belongs to drug oxicity analysis fields, a kind of method for predicting pharmaceuticals toxic effect pattern are provided, by LC₅₀Concentration data and NOCE concentration datas substitute into

Description

A method for predicting the mode of action of drug toxicity

technical field

The invention belongs to the field of drug toxicity and toxicology analysis, and in particular relates to a processing method for predicting drug action mode screening.

Background technique

With the increasingly common occurrence of compound pollution, the mechanism of compound pollution becomes more complicated. According to the research, the ingredients of pharmaceuticals mainly exist in surface water in the concentration range of ppt ~ ppb, and the ingredients in pharmaceuticals that have an effect on the surrounding environment and organisms are biologically active substances (APIs) in pharmaceuticals. Active compounds have serious potential impact on the environment due to factors such as high usage rate and large environmental discharge, and the potential impact of this kind of pharmaceuticals can be compared with the harm of agricultural chemicals to the environment. The effects of these biologically active substances has attracted public and scientific attention. At the same time, given the limited toxicological data available through public channels at this stage, the toxicity evaluation of common drugs is an important part of the preclinical safety evaluation of new drugs, which is directly related to human health and the fate of drugs; The evaluation and research in it have become the focus of attention of drug administration departments and pharmaceutical manufacturers in all countries in the world. Traditional toxicological experimental methods for drug toxicity evaluation are difficult to meet the needs of high-throughput screening in modern drug development due to their shortcomings such as long experimental cycle, high cost, low sensitivity, and the need to consume a large number of experimental animals, and urgently need to be developed. A new toxicity assessment method. It is of vital significance to study how to evaluate the toxicity of drugs in a timely, accurate and rapid manner in the early stage of drug development to shorten the cycle of drug chronic toxicity tests, reduce development costs, improve the hit rate of new drug development, and protect human health.

The toxicological effect mechanism of toxic substances in common pharmaceuticals is much more complicated than the mechanism of environmental behavior. Not only do various interactions occur between pollutants in the environment, but they also manifest as different types of effects such as antagonism, synergy, addition, and independence. It also interacts with biological components, leading to different mechanisms of action such as absorption, enrichment, synthesis, fixation, diffusion, avoidance, detoxification; this is due to toxicological effects, environmental behavior, and biological attributes (such as species , gender, age, individual, cells, target organs, etc.) and many other influences. Therefore, understanding the toxic action mode MOA (mode of action) is the basis and premise of establishing a toxicological effect QSAR (quantitative structure-activity relationship) model.

Drug toxicity MOA usually refers to a series of physiological and behavioral modes of action of organisms caused by adverse reactions, and pays more attention to the apparent characteristics of organisms under the action of active substances APIs in pharmaceuticals. The determination of its specific type usually requires comprehensive information from various aspects, such as joint toxicity studies, acute toxicity syndrome, dose-response relationship, toxicological literature data, etc.

With the development of computers and mathematics in the fields of toxicology and drug discovery, some scholars will judge the drug's mode of action based on the drug's molecular formula, structural formula, molecular structural features, main active ingredients, properties, and the interaction target between the drug and the organism. , and then establish a QSAR model to predict drug toxicity. However, the process of judging the MOA of a drug through molecular structural features often has many inconveniences, and the accuracy of the prediction results still needs to be further improved.

Contents of the invention

In order to make up for the deficiencies of the prior art, the present invention provides a method for quickly identifying the MOA of pharmaceuticals with high accuracy of evaluation results, which is of great significance for shortening the test period and reducing the cost of drug development.

In order to achieve the above object, the present invention adopts the following technical scheme: a method for predicting the mode of action of drug toxicity, comprising the following steps:

S1. Determine the LC ₅₀ concentration data of the acute toxicity of the drug;

S2. Determine the NOCE concentration data of chronic toxicity of pharmaceuticals;

S3. Substitute the LC ₅₀ concentration data and NOCE concentration data into formula Ⅰ to obtain the R-ACT value;

S4. Take the logarithmic value logR-ACT of the R-ACT value based on 10, and substitute logR-ACT into the evaluation range;

S5. When logR-ACT≤1.5, the drug MOA is an anesthetic compound; when 1.5﹤log R-ACT﹤3, the drug MOA is a transition compound; when log R-ACT≥3, the drug MOA is a reactive compound .

Further, in the step S1, the acute toxicity LC ₅₀ concentration data of traditional Chinese medicines are obtained through acute toxicity experiments or medicine information database.

Furthermore, the LC ₅₀ concentration data is the concentration data of the agent capable of killing 50% of organisms.

Further, in the step S2, the NOCE concentration data of chronic toxicity of traditional Chinese medicines are obtained through chronic toxicity experiments or the medicine information database.

Furthermore, the NOCE concentration data is the maximum non-toxic dose concentration data of the compound on organisms.

The present invention will reversibly change the structure and function of the cell membrane through a certain hydrophobic non-covalent interaction between the drug and the cell membrane, and then produce toxic effects on the organism or the interaction between the drug and the biomacromolecule may be through physical changes Rather than a chemical reaction but no biochemical reaction occurs during the entire toxicity process, the mode of action is defined as narcotic toxicity. In theory, medicines have the ability to enter the organism, so medicines are at least to a certain extent The ability to channel narcotic-type toxicity exists.

The mode of action in which the compound itself or its metabolites can biochemically react with certain structures commonly found in biological macromolecules, that is, the formation of electron-withdrawing groups (electrophilic groups) and biological targets (nucleophilic groups) Covalent bonds, especially in biomacromolecules, such as: nucleophilic groups (amino (-NH ₂ ), hydroxyl (-OH) and sulfhydryl (-SH)) in polypeptides, proteins and nucleic acids. This mode of action is defined as a reaction type effect.

In addition to the above two modes of action, another special mode is: during the entire process of toxic interaction between drugs and organisms, due to toxicological effects, they accept chemical properties, environmental behaviors and biological attributes (such as species, gender, age, individual, cell, Target organs, etc.) and many other influences have biochemical reactions in the entire process of toxicity. Some drugs can form hydrogen bonds with organisms, but their electron-withdrawing groups (electrophilic groups) and biological targets (nucleophilic groups) group) but cannot form a covalent bond mode of action, the present invention refers to this mode of action as anesthesia-response transition (abbreviated as transition).

Compared with the prior art, the method provided by the present invention can quickly predict and screen the MOA of pharmaceuticals, and the accuracy of the evaluation result is high, which can shorten the test cycle to a certain extent, reduce the development cost of the drug, and remove the influence of the toxic action mode of the toxicity prediction model Improving the robustness of the joint toxicity prediction model is of great significance for the establishment of a toxicological effect QSAR model.

Description of drawings

Figure 1 shows the comparative relationship between MOA and R-ACT of different pharmaceuticals.

Detailed ways

The present invention is described in detail below through specific examples, but the protection scope of the present invention is not limited. Unless otherwise specified, the experimental methods used in the present invention are conventional methods, and the experimental equipment, materials, reagents, etc. used can be purchased from chemical companies.

Example 1

Taking 33 known medicines as an example, the corresponding acute and chronic data are obtained according to the acute toxicity test or the medicine information database, according to the formula Calculate the drug R-ACT and its logR-ACT, and classify the MOA of the drug according to the Log R-ACT value. When log R-ACT≤1.5, the MOA of the drug is an anesthetic compound. When 1.5<log R -When ACT<3, the MOA of the drug is a transition compound, and when log R-ACT≥3, the MOA of the drug is a reactive compound. See Table 1 and Figure 1 for details.

Table 1 Pharmaceutical R-ACT and its MOA

Example 2

The method of Example 1 was used to evaluate the R-ACT and MOA of the same drug in different organisms. The evaluation results are shown in Table 2.

Table 2 R-ACT and MOA of the same drug in different organisms

Note: ▲-anesthetic compound ■-reactive compound ●-transitional compound

It can be seen from this embodiment that the same drug exhibits the same MOA for different organisms, and the screening method provided by the present invention has a high accuracy rate.

Application example 1

Aspirin (Aspirin, acetylsalicylic acid) can relieve headaches in the short term through vasodilation, and its effect on dull pain is better than that on sharp pain. Through its structural formula and pharmacological effects, it can be known that its MOA is an anesthetic type. Through the toxicity test of aspirin on water fleas, algae and fish, the LC ₅₀ of aspirin on water fleas = 88mg/L, NOEC = 61mg/L, and these two data are substituted into the formula Through calculation, the R-ACT=1.4mg/L of aspirin to Daphnia, log R-ACT=0.146128036, its mode of action is an anesthetic compound; meanwhile, aspirin has LC ₅₀ =106.7mg/L to algae, NOEC=61mg /L, R-ACT=1.749180328mg/L, log R-ACT=0.242834584, its mode of action is an anesthetic compound; LC ₅₀ of aspirin to fish=150mg/L, NOEC=61mg/L, R-ACT=2.459016393mg/L L, log R-ACT=0.390761424 The mode of action is an anesthetic compound. Combined with R-ACT to determine the MOA of aspirin on three organisms, consistent results were obtained, indicating that the MOA of aspirin is anesthetic.

Application example 2

Ethinyl estradiol is 3-hydroxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17-ol. It has positive and negative feedback effects on the hypothalamus and pituitary gland. Small doses can stimulate the secretion of gonadotropins; large doses can inhibit their secretion, thereby inhibiting the ovulation of sex hormones and sex hormones in the ovary, and achieving anti-fertility effects. Ethinyl estradiol can form hydrogen bonds with organisms, but its electrophilic group cannot form covalent bonds with the pituitary gland, which is in line with the transitional compound action mode. According to data collection, it is known that the LC ₅₀ of ethinyl estradiol on Daphnia is is 5.7mg/L, and NOEC is 0.01mg/L. Substitute these two data into the formula Through calculation, the R-ACT of ethinyl estradiol to Daphnia is 570 mg/L, and the log R-ACT is 2.755874856, and its mode of action is a transitional compound; meanwhile, the LC ₅₀ of ethinyl estradiol to algae is 0.84 mg/L, NOEC is 0.01mg/L, R-ACT＝84mg/L, log R-ACT＝1.924279286, and its mode of action is a transitional compound; LC ₅₀ of ethinyl estradiol to fish is 1.60mg/L, and NOEC is 0.01mg/L; R-ACT=160mg/L, log R-ACT=2.204119983 Its mode of action is a transitional compound. Combined with R-ACT to determine the MOA of ethinyl estradiol on the three organisms, consistent results were obtained, indicating that the MOA was transitional.

Application example 3

Bezafibrate is a blood lipid regulating drug derived from clofibrate, and has two mechanisms of action: ① Increase the activity of lipoprotein esterase and liver esterase, promote the catabolism of very low-density lipoprotein, and make blood triglycerides The level of glycerol is reduced. ②Reduce the secretion of very low density lipoprotein. Lowers LDL and cholesterol by enhancing clearance of receptor-bound LDL. The effect of lowering blood triacylglycerol is stronger than that of lowering blood cholesterol. Can significantly reduce triacylglycerol, cholesterol, low-density lipoprotein, very low-density lipoprotein and apolipoprotein B (ApoB), while increasing high-density lipoprotein and apolipoprotein AI and AII. From its mechanism of action and its chemical formula, it can be known that bezafibrate is a reactive compound that can form a covalent bond with the receptor, thereby regulating the activity of the receptor enzyme, and then achieving the therapeutic effect. Through the toxicity test of bezafibrate to water fleas, algae and fish, the LC ₅₀ of bezafibrate to water fleas is obtained = 100mg/L, NOEC = 0.0001mg/L and these two data are substituted into the formula Through calculation, the R-ACT of bezafibrate to Daphnia = 1000000mg/L, log R-ACT = 6, and its mode of action is a reactive compound; in addition, the LC ₅₀ of bezafibrate to algae = 100mg/L L, NOEC=0.0001mg/L, R-ACT=1000000mg/L, log R-ACT=6, its mode of action is a reactive compound; LC ₅₀ of bezafibrate to fish >100mg/L, NOEC=0.0001mg/L L, R-ACT＝1000000mg/L, log R-ACT＝6, its MOA is a reactive compound; combined with R-ACT to determine the MOA of bezafibrate on three organisms, consistent results were obtained, indicating that its MOA is reactive.

The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope of the disclosure of the present invention, according to the present invention Any equivalent replacement or change of the created technical solution and its inventive concept shall be covered within the scope of protection of the present invention.

Claims (5)

1. A method for predicting drug toxicity mode of action, comprising the following steps: S1. Determine the LC ₅₀ concentration data of the acute toxicity of the drug; S2. Determine the NOCE concentration data of chronic toxicity of pharmaceuticals; S3. Substitute the LC ₅₀ concentration data and NOCE concentration data into formula Ⅰ to obtain the R-ACT value; S4. Take the logarithmic value logR-ACT of the R-ACT value based on 10, and substitute logR-ACT into the evaluation range; S5. When log R-ACT≤1.5, the drug MOA is an anesthetic compound; when 1.5﹤log R-ACT﹤3, the drug MOA is a transition compound; when log R-ACT≥3, the drug MOA is a reactive compound compound. 2 . The method according to claim 1 , characterized in that, in the step S1 , the LC ₅₀ concentration data of acute toxicity of traditional Chinese medicines are obtained through acute toxicity experiments or medicine information database. 3 . 3. The method according to claim 1, wherein the _LC50 concentration data is the concentration data of the medicament capable of killing 50% of organisms. 4. The method according to claim 1, characterized in that, in the step S2, the NOCE concentration data of chronic toxicity of traditional Chinese medicines are obtained through chronic toxicity experiments or a drug information database. 5. The method according to claim 1, wherein the NOCE concentration data is the maximum non-toxic dose concentration data of the compound on the organism.