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

A kind of method for predicting pharmaceuticals toxic effect pattern Download PDF

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Publication number
CN108268749A
CN108268749A CN201810047734.3A CN201810047734A CN108268749A CN 108268749 A CN108268749 A CN 108268749A CN 201810047734 A CN201810047734 A CN 201810047734A CN 108268749 A CN108268749 A CN 108268749A
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pharmaceuticals
act
concentration
moa
toxicity
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CN201810047734.3A
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董玉瑛
方政
赵晶晶
孙国权
邹学军
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Dalian Minzu University
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Dalian Nationalities University
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures

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  • Chemical & Material Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Computing Systems (AREA)
  • Theoretical Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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 kind of method for predicting pharmaceuticals toxic effect pattern
Technical field
The invention belongs to drug toxicity and toxicity test field, and in particular to the processing for the prediction that drug binding mode is screened Method.
Background technology
With more prevalentization that combined pollution occurs, combined pollution mechanism then becomes more complicated.It was found that pharmaceuticals Ingredient is mainly prevalent in ppt~ppb concentration ranges in surface water, and is worked in pharmaceuticals to ambient enviroment and biology Ingredient be bioactive substance (APIs) in pharmaceuticals, as the bioactive compound in pharmaceuticals, due to its use The factors such as rate height and environmental emission amount are big to environment there are serious potential impact, and this pharmaceuticals potential impact and chemurgy Product can mention in the same breath the harm of environment, and effect produced by these bioactive substances has caused the public and Ke The concern of educational circles.At the same time, in view of toxicology data is seldom as obtained by public channel at this stage, conventional pharmaceutical product poison Property evaluation be new drug preclinical safety evaluation important content, directly concerning the mankind health and drug destiny；For medicine The evaluation in the environment of product toxicity and the focus that research has become countries in the world medicine management department and pharmaceuticals manufacturer attractes attention. The conventional toxicological experiment method of pharmaceuticals toxicity assessment is traditionally used for because its experimental period is long, cost is more, sensitivity is low, needs The defects of consuming many experiments animal and be difficult to meet the needs of carrying out high flux screening in modern medicines exploitation, urgently development is new Toxicity assessment method.Research how drug development early stage in time, accurate, Fast Evaluation drug toxicity, for shortening medicine The object chronic toxicity test period reduces development cost, improves new drug development hit rate and human health is protected all to have and extremely closes weight The meaning wanted.
The toxicological effect mechanism of toxicant in conventional pharmaceutical product, ring more more complex than the mechanism of environmental behaviour Various reciprocations not only occur in border between polluter, show as the different roles types such as antagonism, collaboration, adduction and independence, Reciprocation also occurs between biological components, the different roles such as leads to absorb, be enriched with, synthesize, fixing, spreading, avoiding, detoxifying Mechanism；This is because toxicological effect is by physicochemical property, environmental behaviour and biological attribute (such as kind, gender, the age, individual, thin Born of the same parents, target organ etc.) etc. various influences.Therefore, understanding toxic effect pattern MOA (mode ofaction), is to establish toxicity Learn the basis and premise of effect QSAR (quantitative structure-activity relationship) model.
Pharmaceuticals toxicity MOA is often referred to cause the effect mould in a series of physiology of organism and behavior when adverse reaction occurs Formula, more focused on the appearance features of the lower organism of active material APIs effects in pharmaceuticals.The determining of its concrete type usually will Comprehensive various information, such as joint toxicity research, acute toxicity syndrome, dose-response relationship, toxicology data in literature Deng.
As computer and mathematics are in the development of toxicology and field of drug discovery, some scholars can pass through the molecule of drug Target site between formula, structural formula, molecular characterization and main active, property and drug and organism judges medicine The binding mode of object, and then establish QSAR models and drug toxicity is predicted, however go to judge medicine by molecular characterization The process of the MOA of object is often there are inconvenience, and the accuracy of prediction result is promoted there is still a need for further.
Invention content
To make up the deficiencies in the prior art, the present invention provides a kind of method and assessments that can quickly screen pharmaceuticals MOA As a result accuracy is high, for shortening the test period, reduces drug development cost and is of great significance.
To achieve the above object, the present invention adopts the following technical scheme that：A kind of side for predicting pharmaceuticals toxic effect pattern Method includes the following steps：
S1. pharmaceuticals acute toxicity LC is determined50Concentration data；
S2. pharmaceuticals chronic toxicity NOCE concentration datas are determined；
S3. by LC50Concentration data and NOCE concentration datas substitute into formula I, obtain R-ACT values；
S4. R-ACT value denary logarithm value logR-ACT are taken, logR-ACT is substituted into scope of assessment；
S5. when logR-ACT≤1.5, pharmaceuticals MOA is anesthesia type compound；When 1.5 ﹤ log R-ACT ﹤ 3, pharmaceuticals MOA is transiens compound；When log R-ACT >=3, pharmaceuticals MOA is response type compound.
Further, the step S1 chinese medicine drugs acute toxicities LC50Concentration data passes through acute toxicity testing or medicine It is obtained in product information bank.
Further, the LC50Concentration data is the drug concentration data that can kill 50% biology.
Further, the step S2 chinese medicine drugs chronic toxicity NOCE concentration datas pass through long term toxicity test or medicine It is obtained in product information bank.
Further, the NOCE concentration datas are the maximal non-toxic Dosages concentration data of compound on organism body.
The present invention is reversible to change cell by by certain hydrophobicity noncovalent interaction between drug and cell membrane The structure and function of film, and then the interaction between organism generation toxic effect or drug and large biological molecule may lead to It crosses physical change rather than chemical reaction but there is no the binding mode that biochemical reaction occurs in entire toxicity process Anesthesia type toxic effect is defined as, theoretically, pharmaceuticals have the ability for entering organism, so pharmaceuticals are certain All at least there is the ability of guiding anesthesia type toxicity in degree.
By compound in itself or its metabolite, biology can occur with being prevalent in certain structures of large biological molecule The binding mode of chemical reaction, i.e. electron withdrawing group (electrophilic group) form covalent bond with biological target position (nucleophilic group), especially It is large biological molecule, such as：Nucleophilic group (amino (- NH in polypeptide, protein and nucleic acid2), hydroxyl (- OH) and sulfydryl (- SH)) this binding mode is defined as response type effect.
In addition to both the above binding mode, another special pattern is：Drug is with biology in entire toxicity process Since toxicological effect is by physicochemical property, environmental behaviour and biological attribute (such as kind, gender, age, individual, cell, target organ Deng) etc. it is various influence biochemical reaction has occurred in entire toxicity process, some drugs can be with organism Hydrogen bond is formed, but its electron withdrawing group (electrophilic group) cannot form the effect mould of covalent bond with biological target position (nucleophilic group) This binding mode is known as anesthesia-response type transitional function (abbreviation transiens) by formula, the present invention.
Compared with prior art, method provided by the invention can screen pharmaceuticals MOA, assessment result accuracy with fast prediction It is higher, the test period can be shortened to a certain extent, reduce the development cost of drug, release toxicity prediction model toxic effect pattern The limitation of influence improves the steady type of joint toxicity prediction model, is of great significance to establishing toxicological effect QSAR models.
Description of the drawings
Fig. 1 is the contrast relationship of different pharmaceuticals MOA and R-ACT.
Specific embodiment
The present invention is described in detail, but do not limit the scope of the invention below by specific embodiment.Unless otherwise specified, originally Experimental method is conventional method used by invention, and experiment equipment used, material, reagent etc. can chemically company be bought.
Embodiment 1
By taking pharmaceuticals known to 33 kinds as an example, it is corresponding anxious, slow that its is obtained according to acute toxicity testing or pharmaceuticals information bank Property data, according to formulaDrug R-ACT and its logR-ACT is calculated, according to Log R-ACT numbers Value classifies the MOA of pharmaceuticals, and as log R-ACT≤1.5, the MOA of pharmaceuticals is anesthesia type compound, as 1.5 ＜ During log R-ACT ＜ 3, the MOA of pharmaceuticals is transiens compound, and as log R-ACT >=3, the MOA of pharmaceuticals is response type Compound.Refer to table 1 and Fig. 1.
Table 1 pharmaceuticals R-ACT and its MOA
Embodiment 2
It is assessed using the method for embodiment 1 for R-ACT and MOA of the pharmaceuticals of the same race in different biologies.It comments Estimate that the results are shown in Table 2.
R-ACT and MOA of 2 pharmaceuticals of the same race of table in different biologies
Note：▲-anesthesia type compound ■-response type compound ●-transiens compound
It is provided by the invention by the present embodiment it is found that same drug shows identical MOA for different organisms Discriminating method accuracy rate is high.
Application examples 1
Aspirin (Aspirin, acetylsalicylic acid) product can be played in a short time by blood vessel dilatation alleviates headache Effect, the medicine is to the effect of dull pain better than the effect to sharp pain.Understand its MOA for anesthesia by its structural formula and pharmacological action Type obtains the toxicity test of water flea, algae and fish LC of the aspirin to water flea by aspirin50=88mg/L, NOEC The two data are substituted into formula by=61mg/LBy the way that R-ACT of the aspirin to water flea is calculated Its binding mode of=1.4mg/L, log R-ACT=0.146128036 is anesthesia type compound；At the same time, aspirin pair Algae LC50=106.7mg/L, NOEC=61mg/L, R-ACT=1.749180328mg/L, log R-ACT=0.242834584 Its binding mode is anesthesia type compound；Aspirin is to the LC of fish50=150mg/L, NOEC=61mg/L, R-ACT= 2.459016393mg/L log R-ACT=0.390761424 binding modes are anesthesia type compound.With reference to R-ACT to Ah Si The woods MOA biological to three kinds judge, has obtained consistent as a result, the MOA for showing aspirin is anesthesia type.
Application examples 2
Ethinyloestradiol (Ethinyl estradiol) is -17 α of 3- hydroxy-19-nors-pregnant steroid -1,3,5 (10)-triolefin -20- Alkynes -17- alcohol.There is positive-negative feedback effect to hypothalamus and hypophysis, low dose can stimulate gonadotrophin secretion；It is large dosage of then press down Its secretion is made, so as to the ovulation of inhibition hormone sex hormone ovary, reaches antifertility action.Ethinyloestradiol can be formed with organism Hydrogen bond, but its electrophilic group cannot form the binding mode of covalent bond with hypophysis, meet transiens compound effects pattern, according to Data collection learns LC of the ethinyloestradiol to water flea50The two data are substituted into formula for 0.01mg/L for 5.7mg/L, NOECIt is 570mg/L to the R-ACT of water flea by the way that ethinyloestradiol is calculated, log R-ACT are 2.755874856 its binding mode is transiens compound；At the same time ethinyloestradiol is to the LC of algae50For 0.84mg/L, NOEC For 0.01mg/L, R-ACT=84mg/L, its binding mode of log R-ACT=1.924279286 is transiens compound；Alkynes is female Alcohol is to fish LC50=1.60mg/L, NOEC 0.01mg/L；R-ACT=160mg/L, log R-ACT=2.204119983 its Binding mode is transiens compound.Judge with reference to the R-ACT MOAs biological to three kinds to ethinyloestradiol, obtained unanimously As a result, show that its MOA is transiens.
Application examples 3
Bezafibrate (Bezafibrate) is there are two types of chlorine shellfish butanoic acid derivative class regulating plasma lipid medicine mechanism of action：1. increase High lipoproteinesterase and liver esterase activity promote the catabolism of very low density lipoprotein, reduce the horizontal of blood triacylglycerol. 2. reduce the secretion of very low density lipoprotein.By the removing of low-density lipoprotein for strengthening combining receptor, reduce low close Spend lipoprotein and cholesterol.It is strong to reduce the effect ratio of blood triacylglycerol and reduce cholesterolemia.Triacylglycerol, courage can be substantially reduced Sterol, low-density lipoprotein, very low density lipoprotein and apolipoprotein B (ApoB), while make high-density lipoprotein and carry fat egg White AI and A II is increased.It can learn that Bezafibrate can form covalent bond with receptor by its mechanism of action and its chemical formula, into And receptor enzymatic activity is adjusted, and then it is a kind of response type compound to reach therapeutic effect.By Bezafibrate to water flea, algae and The toxicity test of fish obtains LC of the Bezafibrate to water flea50=100mg/L, NOEC=0.0001mg/L substitute into the two data FormulaBy the way that the Bezafibrate R-ACT=1000000mg/L to water flea, log R-ACT is calculated =6 its binding mode are response type compound；In addition to this Bezafibrate is to the LC of algae50=100mg/L, NOEC= Its binding mode of 0.0001mg/L, R-ACT=1000000mg/L, log R-ACT=6 is response type compound；Bezafibrate pair The LC of fish50＞ 100mg/L, NOEC=0.0001mg/L, R-ACT=1000000mg/L, log R-ACT=6, MOA are reaction Type compound；Judge with reference to the R-ACT MOAs biological to three kinds to Bezafibrate, obtained consistent as a result, showing it MOA is response type.
The preferable specific embodiment of the above, only the invention, but the protection domain of the invention is not This is confined to, in the technical scope that any one skilled in the art discloses in the invention, according to the present invention The technical solution of creation and its inventive concept are subject to equivalent substitution or change, should all cover the invention protection domain it It is interior.

Claims (5)

  1. A kind of 1. method for predicting pharmaceuticals toxic effect pattern, which is characterized in that include the following steps：
    S1. pharmaceuticals acute toxicity LC is determined50Concentration data；
    S2. pharmaceuticals chronic toxicity NOCE concentration datas are determined；
    S3. by LC50Concentration data and NOCE concentration datas substitute into formula I, obtain R-ACT values；
    S4. R-ACT value denary logarithm value logR-ACT are taken, logR-ACT is substituted into scope of assessment；
    S5. when log R-ACT≤1.5, pharmaceuticals MOA is anesthesia type compound；As 1.5 ﹤ log R-ACT ﹤ 3, pharmaceuticals MOA is Transiens compound；When log R-ACT >=3, pharmaceuticals MOA is response type compound.
  2. 2. the according to the method described in claim 1, it is characterized in that, step S1 chinese medicine drugs acute toxicities LC50Concentration numbers According to by being obtained in acute toxicity testing or pharmaceuticals information bank.
  3. 3. the according to the method described in claim 1, it is characterized in that, LC50Concentration data is can kill 50% biology Drug concentration data.
  4. 4. the according to the method described in claim 1, it is characterized in that, step S2 chinese medicine drugs chronic toxicity NOCE concentration numbers According to by being obtained in long term toxicity test or pharmaceuticals information bank.
  5. 5. according to the method described in claim 1, it is characterized in that, the NOCE concentration datas for compound on organism body most Big toxic effects dose concentration data.
CN201810047734.3A 2018-01-18 2018-01-18 A kind of method for predicting pharmaceuticals toxic effect pattern Pending CN108268749A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113793651A (en) * 2021-08-20 2021-12-14 大连民族大学 Method for improving accuracy of pollutant QSAR model for predicting toxic effect end point value
US12009066B2 (en) * 2019-05-22 2024-06-11 International Business Machines Corporation Automated transitive read-behind analysis in big data toxicology

Citations (2)

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US5827679A (en) * 1995-04-07 1998-10-27 Burlington Research, Inc. Chemical evaluation method
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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827679A (en) * 1995-04-07 1998-10-27 Burlington Research, Inc. Chemical evaluation method
CN105137055A (en) * 2015-08-26 2015-12-09 广东省微生物研究所 Method for predicting and evaluating toxicity of novel non-steroid anti-inflammatory agent pollutant based on daphnia magna toxicity

Non-Patent Citations (1)

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Title
AHLERS,JAN等: ""Acute to chronic ratios in aquatic toxicity - Variation across trophic levels and relationship with chemical structure"", 《ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12009066B2 (en) * 2019-05-22 2024-06-11 International Business Machines Corporation Automated transitive read-behind analysis in big data toxicology
CN113793651A (en) * 2021-08-20 2021-12-14 大连民族大学 Method for improving accuracy of pollutant QSAR model for predicting toxic effect end point value
CN113793651B (en) * 2021-08-20 2023-11-07 大连民族大学 Method for improving accuracy of pollutant QSAR model in predicting toxicity effect end point value

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