CN106407665B - A kind of people's transthyretin chaff interferent virtual screening method - Google Patents
A kind of people's transthyretin chaff interferent virtual screening method Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 54
- 102000009190 Transthyretin Human genes 0.000 title claims abstract description 35
- 108010071690 Prealbumin Proteins 0.000 title claims abstract description 34
- 238000003041 virtual screening Methods 0.000 title claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 272
- 230000000694 effects Effects 0.000 claims abstract description 90
- 238000012216 screening Methods 0.000 claims abstract description 14
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 claims abstract description 13
- 229940034208 thyroxine Drugs 0.000 claims abstract description 13
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 238000012549 training Methods 0.000 claims description 24
- 238000012795 verification Methods 0.000 claims description 23
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 claims description 22
- -1 hydroxy halogeno biphenyl class Chemical class 0.000 claims description 19
- 238000002474 experimental method Methods 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- 230000027455 binding Effects 0.000 claims description 12
- 238000009739 binding Methods 0.000 claims description 12
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- 125000003118 aryl group Chemical group 0.000 claims description 9
- 238000012512 characterization method Methods 0.000 claims description 9
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- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 8
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- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 claims description 4
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- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims description 3
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- GVPODVKBTHCGFU-UHFFFAOYSA-N 2,4,6-tribromoaniline Chemical class NC1=C(Br)C=C(Br)C=C1Br GVPODVKBTHCGFU-UHFFFAOYSA-N 0.000 description 3
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- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 108010048889 Thyroxine-Binding Proteins Proteins 0.000 description 2
- 102000009488 Thyroxine-Binding Proteins Human genes 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UXOOFXUEODCAIP-UHFFFAOYSA-N 1,2,3-tribromo-5-(3,4,5-tribromophenyl)benzene Chemical group BrC1=C(Br)C(Br)=CC(C=2C=C(Br)C(Br)=C(Br)C=2)=C1 UXOOFXUEODCAIP-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 241000024188 Andala Species 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 108010022355 Fibroins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101000772194 Homo sapiens Transthyretin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
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- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000005686 electrostatic field Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 239000003256 environmental substance Substances 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000012757 flame retardant agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 102000056556 human TTR Human genes 0.000 description 1
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- 238000013332 literature search Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- ARERIMFZYPFJAV-UHFFFAOYSA-N tetrabromodiphenyl ethers Chemical compound C1=CC(Br)=CC=C1OC1=CC=C(Br)C(Br)=C1Br ARERIMFZYPFJAV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention discloses a kind of virtual screening methods of people's transthyretin chaff interferent, belong to Assays for Screening Environmental Endocrine Disruptors method field.Its virtual screening process is to be primarily based on ten groups chemicals is classified, then it uses quantitative structure activity relationship model prediction per class chemicals to the disturbing effect of people's transthyretin, and then judges whether chemicals there is interference people's transthyretin to transport the ability of thyroxine and the power of interference performance according to the effect value of prediction.The concise flow for screening people's transthyretin chaff interferent that the present invention announces is reasonable, and method is accurate and reliable, is easily achieved sequencing, is applicable to the virtual screening of potential people's transthyretin chaff interferent and potential interference object priority level initializing in application domain.
Description
Technical field
The present invention relates to a kind of people's transthyretin chaff interferent virtual screening methods, belong to environment incretion interferent
Screening technique field.
Background technology
In the world, latency environment endocrine disrupting activity is always by the important finger as evaluation organic chemicals health risk
One of mark.Organic chemicals interference thyroid hormone (TH) system is one of the important mechanisms of its disturbance endocrine system.TH pairs
The processes such as vertebrate growth, development, differentiation, heat have important regulating and controlling effect.Under normal physiological conditions, TH need by
Transthyretin (TTR, TBG, ALA) is transported to target tissue, could generate the biological effect of TH transductions.However, one
A little substances can influence TH homeostasises by competing the approach of transporter binding site with TH, and then generate toxicological effect, this
Substance belongs to Thyroid Hormone Disruptors (Thyroid disrupting chemicals, TDCs).The TDCs of reference state can quilt
The tissues such as placenta are transported to, it is horizontal to reduce these tissue Ts H.Therefore, it is necessary to which screening can from chemicals used in everyday
The substance that transporter binding site is competed with TH, to reduce interference of these organic chemicals to TH systems.
Studies have shown that TDCs is weak compared with the interference activity to TTR to the interference activity of TBG and ALA, part TDCs can be in nM water
Flat interference TTR (Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM.Environmental
chemicals and thyroid function.Eur J Endocrinol,2006,154(5):599-611).In addition,
In human body, TTR is also responsible for transport TH and enters cerebrospinal fluid through blood-brain barrier and enter in fetus body through placental barrier.Therefore,
Need to pay close attention to TDCs by interfering the approach of TTR to influence the possibility and degree of TH homeostasises.
In the past twenty years, thyroid gland is transported by more than 100 kinds of organic chemicals of experiment test and TH competitive bindings
The ability of fibroin, wherein having the binding ability ratio TH of more than 20 kinds of TDCs and (hTTR) strong.But mankind's chemistry used in everyday
Product more than 140,000 kind, and be increasing every year (Rud é n C, Hansson SO.Registration, Evaluation,
and Authorization of Chemicals(REACH)is but the first step-how far will it
take usSix further steps to improve the European chemicals
legislation.Environ Health Perspect,2010,118(1):6-10), which can be interfered in these chemicals
People and other vertebrate TH homeostasises become focus of people's attention.Currently, evaluation organic chemicals and TH competitive bindings
The method of TTR abilities mainly exposes experimental method and in vitro technique in vivo.But it is numerous, every in face of organic chemicals to be evaluated
Kind organic chemicals may interfere with the present situation of a variety of biologies and multiple targets of the same organism of interference, it is necessary to develop high throughput
Evaluation method meets this evaluation demand.Further, since the method for measuring faces the problem of of high cost, time-consuming, also
" 3R " principle that Animal Experimental Ethical may be violated, makes the non-experimental method of development seem more to obtain organic chemicals risk information
Come more urgent.Therefore, it is necessary to develop a kind of overcoming the shortcomings of current method with the non-experimental evaluation method of high pass flow characteristic.
(quantitative) activity-structure correlation has been used successfully to predict a variety of parameters that can describe pollutant environmental behaviour, such as air-octanol
Water partition coefficient, organic chemicals living being concentration ratio etc..Qualitative activity-structure correlation technique is applied to prediction and screening tool
The organic chemicals of potential source biomolecule effect are the forward positions of international research in recent years.
Literature search the result shows that, be related to the domestic and international patent of TTR primarily with regard to treating and preventing and transport thyroxine egg
White starch prevents transthyretin accidentally folding and transthyretin extracting method etc..It is completed in the present invention
Before, about screening there is hTTR the patent of active TDCs to be interfered to have not been reported.It is ground about the TDCs and TTR models to interact
Studying carefully has seven, wherein five papers are related to brominated flame-retardant, two papers are related to perfluor and polyfluoro class chemicals.Papa et al.
(Papa E,Kovarich S,Gramatica P.QSAR modeling and prediction of the endocrine-
disrupting potencies of brominated flame retardants.Chem Res Toxicol,2010,23
(5):The quantitative model of hTTR disturbing effects can be predicted by 946-954) being constructed based on 17 brominated flame-retardants.The spy of prediction model
Sign is that the disturbing effect of brominated flame-retardant is characterized using two molecular descriptors；Yang et al. (Yang WH, Shen S, Mu LL,
Yu HX.Structure-activity relationship study on the binding of PBDEs with
thyroxine transport proteins.Environ ToxicolChem,2011,30(11):2431-2439) it is based on 28
A polybrominated diphenyl ethers and its Metabolism of hydroxyl content (wherein 16 organic chemicals are active) are divided using molecular similarity index is compared
Analysis method constructs the three-dimensional prediction model that can predict hTTR disturbing effects.Prediction model be characterized in using volume field, electrostatic field,
Hydrophobic field and hydrogen bond receptor field describe the disturbing effect of polybrominated diphenyl ethers and its Metabolism of hydroxyl content as descriptor；Kovarich etc.
People (Kovarich S, Papa E, Gramatica P.QSAR classification models for the
prediction of endocrine disrupting activity of brominated flame retardants.J
Hazard Mater,2011,190(1-3):106-112；Kovarich S,Papa E,Li J,Gramatica P.QSAR
classification models for the screening of the endocrine-disrupting activity
of perfluorinated compounds.SAR QSAR Environ Res.2012,23(3-4):207-220) it is based on 29
(wherein 11 organise for a brominated flame-retardant (wherein 17 organic chemicals are active) and 19 perfluors and polyfluoro class chemicals
Product are active) disaggregated models of hTTR disturbing effects is constructed respectively.Prediction model is characterized in describing using two molecules
Brominated flame-retardant is divided into inactive, medium activity and high activity three classes by symbol；And characterize model prediction accuracy and model is answered
Use domain.
Recently, Papa et al. (Papa E, Kovarich S, Gramatica P.QSAR prediction of the
competitive interaction of emerging halogenated pollutants with human
transthyretin.SAR QSAR Environ Res.2013,24(4):599-615) it is based on 53 organic chemicals (29
Brominated flame-retardant (wherein 17 organic chemicals are active) and 24 perfluors and polyfluoro class chemicals (wherein 15 organic chemistry
Product are active)) construct a disaggregated model.Classification prediction model is characterized in using three molecular descriptors by brominated flame retardant
Agent is divided into inactive, medium activity and high activity three classes；And characterize model prediction accuracy；In addition, also based on there is effect
32 organic chemicals construct Quantitative Prediction Model, it is characterized in that describing brominated flame-retardant and complete using three molecular descriptors
The disturbing effect of fluorine and polyfluoro class chemicals；Characterize models fitting goodness, robustness, predictive ability and model application domain；Easily
(QSAR of Yi Zhongsheng, Li Lianchen, Ye Tingwen, Liu Hongyan, hydroxyl polybrominated diphenyl ethers bioactivity of not reaching the clouds study to loyalty victory et al.
Guilin University of Technology journal .2011,31 (3)：430-438) the disturbing effect number based on 14 kinds of hydroxyl polybrominated diphenyl ethers and hTTR
According to constructing the prediction model of three parameters using multiple linear regression analysis method.
Yang et al. (Yang XH, Xie HB, Chen JW, Li XH.Anionic Phenolic Compounds Bind
Stronger with Transthyretin than Their Neutral Forms:Nonnegligible Mechanisms
in Virtual Screening of Endocrine Disrupting Chemicals.Chem Res Toxicol,2013,
26(9):1340-1347) ionizable organic chemicals and hTTR are had studied by model organic chemicals of phenols organic chemicals
Interaction mechanism, find anion state phenols organic chemicals be better than corresponding molecular conformation with the interaction of the albumen.
Aromatic ring in phenols organic chemicals can form cation-π interaction with the residue of hTTR.The result is to carry out classification prediction
Provide mechanistic information.
Currently, there are following deficiencies for the model about prediction TDCs to hTTR disturbing effects：
(1) single prediction model only is constructed, does not form the screening strategy and method of system；
(2) brominated flame-retardants such as polybrominated diphenyl ethers and hydroxyl polybrominated diphenyl ethers and perfluor and polyfluoro class chemistry be may be only available for
Product.
The demand of potential hTTR chaff interferents is screened for above deficiency and needing.The present invention from following aspects into
Improvement is gone：
(1) multiple types chemicals is collected to hTTR disturbing effect data, and chemicals includes halogenated biphenyl and hydroxy halogeno connection
It is benzene class, hydroxyl base dioxin, insecticide, halogenated biphenyl ether and hydroxy halogeno biphenyl ethers, halogenated phenols, Halogenated bisphenol A class, more
Fluoro and perfluorinated substituted carboxylic acids or sulphonic acids chemicals and halogenated alkane；Construct hTTR chaff interferents screening strategy and method.That is base
Chemicals is classified in 10 groups, then uses Quantitative structure-activity relationship model prediction per class chemicals to hTTR
Disturbing effect；
(2) it is directed to the different characteristics of different classes of organic chemicals and hTTR interactions, selects molecule description respectively
Symbol builds prediction model based on multiple linear regression analysis method；It is fitted using internal verification and external authentication methods assessment models excellent
Degree, robustness and predictive ability；And the application domain of model is defined using lever value method.
Beneficial effects of the present invention：
(1) the hTTR chaff interferent virtual screening strategies and method suitable for multiple types chemicals are constructed；
(2) molecular descriptor is easy to calculate；Prediction model is succinctly transparent, is easily achieved sequencing；According to economic cooperation with
Development institution publication builds the directive/guide with verification about Study on Quantitative Structure-Activity Relationship correlation model, characterizes the fitting of prediction model
Goodness, robustness and predictive ability define the application domain of model.
Invention content
It is potential the technical problem to be solved by the present invention is to establish a kind of reliable, easy, quick, cheap differentiation and screening
The strategy and method of hTTR chaff interferents.The technical issues of specifically solving three aspects：
(1) suitable chemicals classification group is chosen；
(2) accurately and reliably Quantitative Prediction Model is built；
(3) rational hTTR chaff interferents virtual screening strategy and implementation method are built.
According to the similar substance of molecular structure, there are similar physicochemical properties, environment to return and become and ecological toxicology effect
The principle answered, using mathematical model characterization molecular structure and its physicochemical property, the inherence of environmental behaviour and ecological toxicology parameter
It contacts (such as structure-activity relation (SAR) and Quantitative structure-activity relationship (QSAR)), is to advocate the chemistry used in the world
One of product physicochemical property, environmental behaviour and ecotoxicological effect supplemental characteristic acquiring technology.This theoretical core is to be based on one
The data for determining sample number disclose the internal relation between molecular structure and effect, and then use the statistical method structure of science
Build the mathematical relationship between molecular structure and chemicals physicochemical property, environmental behaviour and ecotoxicological effect parameter.Based on this,
The present invention is first from literature's store organic pollution to the experimental data of hTTR disturbing effects；It is closed in Analysis interference effect and structure
It on the basis of system, filters out 10 groups and classifies to chemicals, then use multiple linear regression analysis method to build quantitative pre-
Survey model；Model prediction is finally used to judge chemistry to hTTR disturbing effects, and then according to the effect value of prediction per class chemicals
Whether product have the ability of interference hTTR transhipment thyroxine and the power of interference performance.
Technical scheme of the present invention：
A kind of people's transthyretin chaff interferent virtual screening method, steps are as follows：
(1) organic chemicals data are collected
108 kinds of organic chemicals are collected to hTTR disturbing effect data, which combined by competitive radioligand
Mode obtains, the condition of acquisition：PH=8.0, radioligand are125The thyroxine of I labels125I-T4With hTTR albumen concentration
For 30nM；Wherein, 62 kinds of organic chemicals have detectable interference activity；Organic chemicals with125I-T4HTTR is competed to combine
The ability in site uses half competitive effect concentration (IC50) indicate, IC50To incite somebody to action125I-T450% is replaced out from hTTR binding sites
When the organic chemicals concentration that needs；
108 kinds of organic chemicals include halogenated biphenyl and hydroxy halogeno biphenyl class, Qiang Ji dioxins, insecticide, halogenated
Biphenyl Ether and hydroxy halogeno biphenyl ethers, halogenated phenols, Halogenated bisphenol A class, polyfluoro generation and perfluorinated substituted carboxylic acids and sulphonic acids and halogen
For alkanes；
(2) it chooses crucial group, carry out chemicals classification
In terms of choosing suitable classification group, based on the group that Dragon6.0 softwares calculate, analyzes and live with interference
The organic chemicals structure feature of property.The meaning of functional group and functional group according to occurrence rate more than 10%, it can be seen that description
Symbol has mainly distinguished aromatic hydrocarbons and alkane；In addition, in terms of substituent group, major embodiment polar group or ionogen and halogen
Substituted importance.Mechanism of action analysis result shows (Yang XH, Xie HB, Chen JW, Li XH.Anionic
Phenolic Compounds Bind Stronger with Transthyretin than Their Neutral Forms:
Nonnegligible Mechanisms in Virtual Screening of Endocrine Disrupting
Chemicals.Chem Res Toxicol,2013,26(9):1340-1347), aromatic ring can be with hTTR in organic chemicals structure
Cation-π interaction is formed, since, without aromatic ring structure, thus it is mutual to form cation-π with hTTR in alkane structure
Effect, this is that the interaction of alkanes organic chemicals and hTTR is caused to be weaker than the mutual of aromatic hydrocarbons organic chemicals and hTTR
The one of the major reasons of effect.
Ionogen is in organic chemicals and the effect in hTTR cohesive process, under physiology or experiment condition,
Hydroxyl (- OH), carboxyl (- COOH), sulfonic group and sulfinic acid base (- SO2OH and-SOOH) etc. groups can be dissociated into anion, should
Anionic group can be with the lysine residue side chain-NH at hTTR active sites3 +Ion Thermodynamic parameters are formed, cause to organise
Product anionic form is better than corresponding molecular conformation with the interaction of hTTR.In addition, in organic chemicals molecular structure
Halogen group can be organised by forming halogen key and halogen hydrogen bond with hTTR and influencing organic halogen by inductive effect and hydrophobic effect
Product interact with TTR.Therefore, aromatic hydrocarbons and alkane, organic chemicals can be dissociated and organic chemicals can not be dissociated, halogenated had
Chemical machine product have different mechanism of action from non-halogenated organic chemicals and hTTR.
According to nitrogen-atoms number nN, aromatic carbon atom number nCar, phenolic hydroxyl group number nArOH, benzoxy number nArCOOH, hydroxyl
Base number nROH, carboxyl number nRCOOH, sulfonic group number nSO3H, sulfinic acid base number nSO2H, the cyclosubstituted halogen number n of benzeneArX
With halogen number nXClassify to 108 kinds of organic chemicals, sorting technique is as follows：
The first step：108 kinds of organic chemicals are obtained in hTTR disturbing effect data, first, first judging n in step (1)N
Whether it is 0, works as nNWhen=0, need to further it judge；Work as nNWhen ≠ 0, the organic chemicals of nitrogen atom are excluded；
Second step：Work as nNWhen=0, then judge nCarWhether it is more than 0, organic chemicals is divided into aromatics organic chemicals
With non-aromatic class organic chemicals, work as nCar>When 0, organic chemicals are aromatics organic chemicals；As organic chemicals nCar=
When 0, organic chemicals are non-aromatic class organic chemicals；
Third walks：For aromatics organic chemicals, then judge nArOH+nArCOOHWhether it is more than 0, filters out phenolic hydroxy group
Or the organic chemicals of benzoxy；As organic chemicals nArOH+nArCOOH>When 0, this organic chemicals is phenolic hydroxy group or benzene
The organic chemicals of formyl are first kind organic chemicals；As organic chemicals nArOH+nArCOOHWhen=0, this organic chemistry
Product further judge；Work as nArOH+nArCOOH=0 aromatics organic chemicals, then judge nROH+nRCOOH+nSO2OH+nSOOHIt is whether big
In 0, the aromatics organic chemicals of branch hydroxyl, carboxyl, sulfonic group or sulfinic acid base are filtered out；
As organic chemicals nROH+nRCOOH+nSO2OH+nSOOH>When 0, this organic chemicals is branch hydroxyl or carboxyl or sulphur
The aromatics organic chemicals of acidic group or sulfinic acid base are the second class organic chemicals；As organic chemicals nROH+nRCOOH+
nSO2OH+nSOOHWhen=0, this organic chemicals is further judged；
To nROH+nRCOOH+nSO2OH+nSOOH=0 aromatics organic chemicals, then judge nArXWhether it is more than 0, filters out halogen
For aromatic hydrocarbons；As organic chemicals nArX>When 0, this organic chemicals is halogenated aryl hydrocarbon, is third class organic chemicals；When organising
Product nArXWhen=0, this organic chemicals is excluded；
4th step：For alkanes organic chemicals, n is judgedROH+nRCOOH+nSO2OH+nSOOHWhether it is more than 0, filters out and contain
The organic chemicals of hydroxyl or carboxyl or sulfonic group or sulfinic acid base；As organic chemicals nROH+nRCOOH+nSO2OH+nSOOH>When 0,
This organic chemicals is the organic chemicals of hydroxyl or carboxyl or sulfonic group or sulfinic acid base, is the 4th class organic chemicals；
As organic chemicals nROH+nRCOOH+nSO2OH+nSOOHWhen=0, this organic chemicals is further judged；
To nROH+nRCOOH+nSO2OH+nSOOH=0 alkanes organic chemicals, then judge nXWhether it is more than 0, filters out halogen
For alkane；As organic chemicals nX>When 0, this organic chemicals is halogenated alkane, is the 5th class organic chemicals；When organising
Product nXWhen=0, this organic chemicals is excluded；
Organic chemicals can be divided into five classes by effect power by this ten crucial groups：
1. phenols or benzoic acids organic chemicals；
2. the aromatics organic chemicals of branch hydroxyl or carboxyl or sulfonic group or sulfinic acid base；
3. the not halogenated aryl hydrocarbon organic chemicals of hydroxyl or the groups such as carboxyl or sulfonic group or sulfinic acid base；
4. the alkanes organic chemicals of hydroxyl or the groups such as carboxyl or sulfonic group or sulfinic acid base；
5. the not alkyl halide hydro carbons organic chemicals of hydroxyl or the groups such as carboxyl or sulfonic group or sulfinic acid base.
The present invention is applicable in chemicals range：
1. unazotized organic chemicals
2. arene chemicals：It is mainly substitution functional group with hydroxyl or carboxyl or halogen；
3. alkanes chemicals：It is mainly substitution functional group with hydroxyl or carboxyl or sulfonic group or sulfinic acid base or halogen.
(3) structure and characterization of Quantitative Prediction Model
With taking the relative effect gesture (RP) of logarithm to characterize the ability that TDCs and TH competes hTTR binding sites when modeling, RP is fixed
Justice is：
Wherein：IC50(T4) and IC50(TDCs) thyroxine (T is respectively represented4) and TDCs half competitive effect concentration
(nM).LogRP values are bigger, indicate that the ability of organic chemicals and TH competition hTTR binding sites is stronger.
In order to build the Quantitative Prediction Model that application domain includes inactive chemicals, inactive organic chemicals are interfered
Activity is set as 625000nM (Yang WH, Shen S, Mu LL, Yu HX.2011.Structure-activity
relationship study on the binding of PBDEs with thyroxine transport
proteins.Environ ToxicolChem,30:2431-2439).According to TH and the hTTR effect of Weiss et al. tests
IC50(T4) value be 61nM (Weiss JM, Andersson PL, Lamoree MH, Leonards PE, van Leeuwen SP,
Hamers T.2009.Competitive binding of poly-and perfluorinated compounds to the
thyroid hormone transport protein transthyretin.ToxicolSci 109:206-216.), it can count
Calculate inactive chemicals relative effect gesture logRP=-4.011.
1. calculating molecular descriptor
Optimize organic chemicals molecular structure, the organic chemicals molecular structure based on optimization calculates each organic chemistry
4885 Dragon descriptors of product；Descriptor is pre-processed according to following principle：Removal has the descriptor of missing values；Two
Descriptor correlation is more than 0.99 descriptor, the big descriptor of removal standard deviation；
2. according to the classification results of step (2), constructs aromatics and alkanes organic organic chemicals and hTTR is interfered
The prediction model of effect：Wherein, aromatics organic chemicals prediction model includes 75 organic chemicals, and training set and verification collect
Respectively 61 and 14；Alkanes organic chemicals prediction model includes 33 organic chemicals, training set and verification collection point
It Wei not be 24 and 9；Aromatics and the organic organic chemicals of alkanes are built to hTTR using stepwise multiple linear regression method
The prediction model of disturbing effect；
3. prediction model expression formula：
Aromatics organic chemicals prediction model expression formula is：
LogRP=-3.181+2.515nArOH-8.990×10-1CIC3+3.463Eig15_EA(dm)
+2.723×10-1H7m+6.901×10-1RTs+ (2)
Wherein, nArOHRefer to the number of phenolic hydroxyl group in molecule, CIC3 is molecular information index, and Eig15_EA (dm) is dipole moment
The characteristic value of weighting, H7m are the H autocorrelation exponents of molecular mass weighting, and RTs+ is the R indexes of I-state weightings；
Alkanes organic chemicals prediction model expression formula is：
LogRP=-4.279+3.891 × 10-2H2s–1.961×10-1Mor07m
+5.476×10R8v+ (3)
Wherein, H2s is the H autocorrelation exponents of I-state weightings, and Mor07m is the 3D-MoRSE descriptions of molecular mass weighting
Symbol, R8v+ refer to the R autocorrelation exponents of second order molecular susceptibility weighting；
4. using the related coefficient square (R between experiment value and predicted value2), remove a method cross validation coefficient (Q2 Training set)、
Related coefficient (the Q of external certificate collection2 Verification collection) and root-mean-square error (RMSE) evaluation model the goodness of fit, robustness and prediction
Ability；
The characterization result of aromatics organic chemicals prediction model：Phase relation between the experiment value and predicted value of training set
Several squares of R2 Training set=0.899, the root-mean-square error (RMSE of training setTraining set)=0.662, Q2 Training set=0.863, show that model has
There are the preferable goodness of fit and robustness；The related coefficient Q of external certificate collection2 Verification collection=0.874, R2 Verification collection=0.879, outside is tested
Demonstrate,prove the root-mean-square error RMSE of collectionVerification collection=0.734, show that model has preferable predictive ability.
The characterization result of alkanes organic chemicals prediction model：R2 Training set=0.961, RMSETraining set=0.217, Q2 Training set=
0.940, show that model has the preferable goodness of fit and robustness；Q2 Verification collection=0.932, R2 Verification collection=0.950, RMSEVerification collection=
0.264, show that model has preferable predictive ability；
5. characterizing the application domain of model using Williams figures, Williams figures are indicated by residual and lever value.
The application domain of aromatics organic chemicals prediction model is：Lever value is less than 0.3；Alkanes organic chemicals prediction model is answered
It is with domain：Lever value is less than 0.5.
(4) people's transthyretin chaff interferent virtual screening method
It is using the step of present invention progress hTTR chaff interferent virtual screenings：
1. judging unknown chemicals whether in the mechanism domain of screening technique according to molecular structure group.If in the machine of method
It manages in domain, then unknown organic chemicals is classified based on ten groups；If this cannot not be used in the mechanism domain of method
Method is predicted.
2. according to unknown chemicals classification results, suitable prediction model is selected；Requirement based on prediction model calculates not
Know the molecular descriptor of organic chemicals, and calculates the lever value of unknown organic chemicals according to molecular descriptor, it is more unknown
Whether the lever value of organic chemicals is within the scope of the application domain of model.If unknown organic chemicals are in the application domain range of model
Interior, then the model according to selection calculates logRP value of the unknown organic chemicals to hTTR；If unknown organic chemicals are not in model
Application domain within the scope of, then cannot be predicted with model.
3. judging whether unknown organic chemicals there is interference hTTR to transport the ability of TH and do according to the logRP values of prediction
Disturb the power of ability.
The criterion of interference performance is as follows：
High interference activity：logRP≥-1.00；
Moderate interference activity：-2.00≤logRP<-1.00；
Low interference activity：-4.011≤logRP<-2.00；
Noiseless activity：logRP<-4.011.
Beneficial effects of the present invention：
(1) the hTTR chaff interferent virtual screening strategies and method built is concise, reasonable；
(2) molecular descriptor is simple, is easy to calculate；Prediction model form is concise, is easy to sequencing realization；It is closed according to economy
Make, with the directive/guide about Quantitative structure-activity relationship model construction and verification of development institution publication, to characterize prediction model
The goodness of fit, robustness and predictive ability define the application domain of model.
(3) judge whether unknown chemicals is in the application domain of screening technique twice, improve the accurate of prediction result
Degree and confidence level.
Description of the drawings
Fig. 1 is people's transthyretin chaff interferent structure-activity relation analysis chart.
Fig. 2 is aromatics organic chemicals prediction model training set and verification collection experiment value and predicted value relational graph.
Fig. 3 is alkanes organic chemicals prediction model training set and verification collection experiment value and predicted value relational graph.
Fig. 4 is people's transthyretin chaff interferent screening process figure.
Specific implementation mode
Below in conjunction with technical solution and attached drawing, the specific implementation mode that further illustrates the present invention.
Embodiment 1
The interference of the unmanned transthyretin of 2,4,6- tribromanilines is active (logRP=-4.011).Utilize the present invention
Predict that it interferes that active steps are as follows：
According to the molecular descriptor that Dragon is calculated, the n of 2,4,6- tribromanilinesN=1, it is nitrogenous organic chemicals, no
In the mechanism domain of method, it cannot enter and calculate in next step.
Interference activity of the model prediction 2,4,6- tribromanilines to people's transthyretin cannot be used.
Embodiment 2
Interference activity logRP=-1.871 of 2'- hydroxyls -2,3', 4,4'- the tetrabromo Biphenyl Ether to people's transthyretin
×10-1.Using present invention prediction, it interferes that active steps are as follows：
According to the molecular descriptor that Dragon is calculated, 2'- hydroxyls -2,3', the n of 4,4'- tetrabromo Biphenyl EthersN=0, to be free of
Nitrogen organic chemicals can enter and calculate in next step in the mechanism domain of method；
Its nCar=12>0, it is aromatics organic chemicals, and its nArOH+nArCOOH=1>0, it is phenols organic chemicals,
In the mechanism domain of method, belong to chemicals classification I, can enter and calculate in next step；
According to chemicals classification results, model 1 is selected to carry out Activity Prediction.
According to 2'- hydroxyls -2,3', it is 0.03 that the molecular structure of 4,4'- tetrabromo Biphenyl Ethers, which calculates its lever value, in model 1
Application domain within the scope of (lever value be less than 0.3), therefore, model 1 can be used for predicting 2'- hydroxyls -2,3', 4,4'- tetra- bromo biphenyls
Interference activity of the ether to people's transthyretin：
LogRP=-3.181+2.515nArOH-8.990×10-1CIC3+3.463Eig15_EA(dm)
+2.723×10-1H7m+6.901×10-1RTs+
=-3.181+2.515 × 1-8.990 × 10-1×1.67×10-1+3.463×0
+2.723×10-1×6×10-2+6.901×10-1×1.127
=-2.210 × 10-2
2'- hydroxyls -2,3', 4,4'- tetrabromo Biphenyl Ether logRP=-2.210 × 10 of model prediction-2, experiment value is
LogRP=-1.871 × 10-1, predicted value is with uniformity with experiment value.Judged according to effect value, this organic chemicals has height
Interference activity.Therefore, it is necessary to pay high attention to 2'- hydroxyls -2,3', 4,4'- tetrabromo Biphenyl Ethers are by interfering people to transport thyroxine egg
The mode of white transhipment thyroxine interferes thyroid gland system.
Embodiment 3
Interference activity logRP=-3.354 of 3,3', 4,4', the 5- pentachlorodiphenyl to people's transthyretin.Utilize this
Its interference of invention prediction is active, and steps are as follows：
According to the molecular descriptor that Dragon is calculated, 3,3', the n of 4,4', 5- pentachlorodiphenylsN=0, it organises to be not nitrogenous
Product can enter and calculate in next step in the mechanism domain of method；
Its nCar=12>0, it is aromatics organic chemicals；
nArOH+nArCOOH=0, it is not phenols or benzoic acids organic chemicals；
nROH+nRCOOH+nSO2OH+nSOOH=0, for hydroxyl or the aromatics of carboxyl or sulfonic group or sulfinic acid base are not organic
Chemicals；
nArX=5>0, belong to chemicals classification III in the mechanism domain of method for halogenated aromatic class organic chemicals, it can
It is calculated into next step；
According to chemicals classification results, model 1 is selected to carry out Activity Prediction.
According to 3,3', it is 0.05 that the molecular structure of 4,4', 5- pentachlorodiphenyls, which calculates its lever value, in the application domain of model 1
In range (lever value is less than 0.5).Therefore, model 1 can be used for prediction 3,3', and 4,4', 5- pentachlorodiphenyls transport thyroxine to people
The interference activity of albumen：
LogRP=-3.181+2.515nArOH-8.990×10-1CIC3+3.463Eig15_EA(dm)
+2.723×10-1H7m+6.901×10-1RTs+
=-3.181+2.515 × 0-8.990 × 10-1×8.87×10-1+3.463×0
+2.723×10-1×0+6.901×10-1×1.231
=-3.129
The 3,3' of model prediction, 4,4', 5- pentachlorodiphenyl logRP=-3.129, experiment value logRP=-3.354, in advance
Measured value is with uniformity with experiment value.Judged according to effect value, this organic chemicals has low interference activity.It transports first shape with people
The binding ability of parathyrine albumen is far weaker than natural parathyroid parathyrine, therefore, 3,3', 4,4', 5- pentachlorodiphenyls can only be in high concentration water
Flat (>10-4Mol) just there is the ability of interference people's transthyretin transhipment thyroxine.
Embodiment 4
The interference of the unmanned transthyretin of 3,3', 4,4', 5,5'- hexabromobiphenyl ether is active (logRP=-4.011).
Using present invention prediction, it interferes that active steps are as follows：
According to the molecular descriptor that Dragon is calculated, the n of 3,3', 4,4', 5,5'- hexabromobiphenyl ethersN=0, it is not nitrogenous
Organic chemicals can enter and calculate in next step in the mechanism domain of method；
Its nCar=12>0, it is aromatics organic chemicals；
nArOH+nArCOOH=0, it is not phenols or benzoic acids organic chemicals；
nROH+nRCOOH+nSO2OH+nSOOH=0, for hydroxyl or the aromatics of carboxyl or sulfonic group or sulfinic acid base are not organic
Chemicals；
nArX=6>0, belong to chemicals classification III in the mechanism domain of method for halogenated aromatic class organic chemicals, it can
It is calculated into next step；
According to chemicals classification results, model 1 is selected to carry out Activity Prediction.
It is 0.06 that molecular structure according to 3,3', 4,4', 5,5'- hexabromobiphenyl ethers, which calculates its lever value, in answering for model 1
With (lever value is less than 0.5) within the scope of domain.Therefore, model 1 can be used for 3,3', 4,4', 5,5'- hexabromobiphenyl ether of prediction to people's fortune
The interference activity of thyroxin：
LogRP=-3.181+2.515nArOH-8.990×10-1CIC3+3.463Eig15_EA(dm)
+2.723×10-1H7m+6.901×10-1RTs+
=-3.181+2.515 × 0-8.990 × 10-1×1.652+3.463×0
+2.723×10-1×4.3×10-2+6.901×10-1×5.91×10-1
=-4.247
The 3,3' of model prediction, 4,4', 5,5'- hexabromobiphenyl ether logRP=-4.247, noiseless activity.
Embodiment 5
Interference activity logRP=-2.130 of the perfluor caproic acid to people's transthyretin.Using present invention prediction, it is dry
Disturb that active steps are as follows：
According to the molecular descriptor that Dragon is calculated, the n of perfluor caproic acidN=0, it is not nitrogenous organic chemicals, in method
Mechanism domain in, can enter in next step calculate；
Its nCar=0, it is alkanes organic chemicals；
nROH+nRCOOH+nSO2OH+nSOOH=1>0, it is that hydroxyl or carboxyl or the alkanes of sulfonic group or sulfinic acid base are organic
Chemicals belongs to chemicals classification IV in the mechanism domain of method, can enter and calculate in next step；
According to chemicals classification results, model 2 is selected to carry out Activity Prediction.
It is 0.1 that molecular structure according to perfluor caproic acid, which calculates its lever value, (the lever value within the scope of the application domain of model 2
Less than 0.5).Therefore, model 2 can be used for predicting interference activity of the perfluor caproic acid to people's transthyretin：
LogRP=-4.279+3.891 × 10-2H2s–1.961×10-1Mor07m+5.476×10R8v+
=-4.279+3.891 × 10-2×6.368×10–1.961×10-1×3.37+5.476×10×7×
10-3
=-2.079
According to the perfluor caproic acid logRP=-2.130 of model prediction, experiment value logRP=-2.079, predicted value and reality
It is with uniformity to test value.Judged according to effect value, this organic chemicals has low interference activity.Therefore, perfluor caproic acid is higher
Concentration level (>10-5Mol) just there is the ability of interference people's transthyretin transhipment thyroxine.
Embodiment 6
The unmanned transthyretin interference of tetradecanoic acid is active (logRP=-4.011).Using present invention prediction, it is dry
Disturb that active steps are as follows：
According to the molecular descriptor that Dragon is calculated, the n of tetradecanoic acidN=0, it is not nitrogenous organic chemicals, in method
Mechanism domain in, can enter in next step calculate；
Its nCar=0, it is alkanes organic chemicals；
nROH+nRCOOH+nSO2OH+nSOOH=1>0, have for hydroxyl or carboxyl or the non-aromatic hydrocarbon of sulfonic group or sulfinic acid base
Chemical machine product belong to chemicals classification IV in the mechanism domain of method, can enter and calculate in next step；
According to chemicals classification results, model 2 is selected to carry out Activity Prediction.
It is 0.005 that molecular structure according to tetradecanoic acid, which calculates its lever value, (the lever within the scope of the application domain of model 2
0.5) value is less than.Therefore, model 2 can be used for predicting interference activity of the tetradecanoic acid to people's transthyretin：
LogRP=-4.279+3.891 × 10-2H2s–1.961×10-1Mor07m+5.476×10R8v+
=-4.279+3.891 × 10-2×4.126–1.961×10-1×8.45×10-1+5.476×10×2×
10-3
=-4.175
The tetradecanoic acid logRP=-4.175 of model prediction, noiseless activity.
Embodiment 7
Interference activity logRP=-2.658s of the hexabromocyclododecane β to people's transthyretin.It is predicted using the present invention
Its interference is active, and steps are as follows：
According to the molecular descriptor that Dragon is calculated, the n of hexabromocyclododecane βN=0, it is not nitrogenous organic chemicals,
In the mechanism domain of method, it can enter and calculate in next step；
Its nCar=0, it is alkanes organic chemicals；
nROH+nRCOOH+nSO2OH+nSOOH=0, nX=6 be the not alkyl halide of hydroxyl or carboxyl or sulfonic group or sulfinic acid base
Hydrocarbon belongs to chemicals classification V in the mechanism domain of method, can enter and calculate in next step；
According to chemicals classification results, model 2 is selected to carry out Activity Prediction.
It is 0.4 that molecular structure according to hexabromocyclododecane β, which calculates its lever value, (the thick stick within the scope of the application domain of model 2
0.5) bar value is less than.Therefore, model 2 can be used for predicting interference activity of the hexabromocyclododecane β to people's transthyretin：
LogRP=-4.279+3.891 × 10-2H2s–1.961×10-1Mor07m+5.476×10R8v+
=-4.279+3.891 × 10-2×6.545–1.961×10-1×(-4.198)+5.476×10×1×
10-2
=-2.653
It is logRP=-2.658, experiment value logRP=- according to the hexabromocyclododecane β effect values of model prediction
2.653, predicted value is with uniformity with experiment value.Judged according to effect value, this organic chemicals has low interference activity.Cause
This, hexabromocyclododecane β higher concentration it is horizontal (>10-5Mol) just there is interference people's transthyretin to transport thyroxine
Ability.
Claims (1)
1. a kind of people's transthyretin chaff interferent virtual screening method, which is characterized in that steps are as follows：
(1) organic chemicals data are collected
108 kinds of organic chemicals are collected to hTTR disturbing effect data, which is by competitive radioligand combination
It obtains, the condition of acquisition：PH=8.0, radioligand are125The thyroxine of I labels125I-T4It is a concentration of with hTTR albumen
30nM；Wherein, 62 kinds of organic chemicals have detectable interference activity；Organic chemicals with125I-T4Compete hTTR bound sites
The ability of point uses half competitive effect concentration IC50It indicates, IC50For by 50%125I-T4It replaces out from hTTR binding sites
When required organic chemicals concentration；
108 kinds of organic chemicals include halogenated biphenyl and hydroxy halogeno biphenyl class, Qiang Ji dioxins, insecticide, halogenated biphenyl
Ether and hydroxy halogeno biphenyl ethers, halogenated phenols, Halogenated bisphenol A class, polyfluoro generation and perfluorinated substituted carboxylic acids and sulphonic acids and alkyl halide
Hydro carbons；
(2) it chooses crucial group, carry out chemicals classification
According to nitrogen-atoms number nN, aromatic carbon atom number nCar, phenolic hydroxyl group number nArOH, benzoxy number nArCOOH, hydroxyl
Number nROH, carboxyl number nRCOOH, sulfonic group number nSO2OH, sulfinic acid base number nSOOH, the cyclosubstituted halogen number n of benzeneArXAnd halogen
Plain number nXClassify to 108 kinds of organic chemicals, sorting technique is as follows：
The first step：108 kinds of organic chemicals are obtained in hTTR disturbing effect data, first, first judging n in step (1)NWhether
It is 0, works as nNWhen=0, need to further it judge；Work as nNWhen ≠ 0, the organic chemicals of nitrogen atom are excluded；
Second step：Work as nNWhen=0, then judge nCarWhether it is more than 0, organic chemicals is divided into aromatics organic chemicals and non-aromatic
Fragrant class organic chemicals, work as nCar>When 0, organic chemicals are aromatics organic chemicals；As organic chemicals nCarWhen=0, have
Chemical machine product are non-aromatic class organic chemicals；
Third walks：For aromatics organic chemicals, then judge nArOH+nArCOOHWhether it is more than 0, filters out phenolic hydroxy group or benzene first
The organic chemicals of acidic group；As organic chemicals nArOH+nArCOOH>When 0, this organic chemicals is phenolic hydroxy group or benzoxy
Organic chemicals, be first kind organic chemicals；As organic chemicals nArOH+nArCOOHWhen=0, this organic chemicals is into one
Step judges；Work as nArOH+nArCOOH=0 aromatics organic chemicals, then judge nROH+nRCOOH+nSO2OH+nSOOHWhether 0 is more than, sieve
Select the aromatics organic chemicals of branch hydroxyl, carboxyl, sulfonic group or sulfinic acid base；
As organic chemicals nROH+nRCOOH+nSO2OH+nSOOH>When 0, this organic chemicals is branch hydroxyl or carboxyl or sulfonic group
Or the aromatics organic chemicals of sulfinic acid base, it is the second class organic chemicals；As organic chemicals nROH+nRCOOH+nSO2OH+
nSOOHWhen=0, this organic chemicals is further judged；
To nROH+nRCOOH+nSO2OH+nSOOH=0 aromatics organic chemicals, then judge nArXWhether it is more than 0, filters out halogenated virtue
Hydrocarbon；As organic chemicals nArX>When 0, this organic chemicals is halogenated aryl hydrocarbon, is third class organic chemicals；Work as organic chemicals
nArXWhen=0, this organic chemicals is excluded；
4th step：For alkanes organic chemicals, n is judgedROH+nRCOOH+nSO2OH+nSOOHWhether it is more than 0, filters out hydroxyl
Or the organic chemicals of carboxyl or sulfonic group or sulfinic acid base；As organic chemicals nROH+nRCOOH+nSO2OH+nSOOH>When 0, this has
Chemical machine product are the organic chemicals of hydroxyl or carboxyl or sulfonic group or sulfinic acid base, are the 4th class organic chemicals；When having
Chemical machine product nROH+nRCOOH+nSO2OH+nSOOHWhen=0, this organic chemicals is further judged；
To nROH+nRCOOH+nSO2OH+nSOOH=0 alkanes organic chemicals, then judge nXWhether it is more than 0, filters out alkyl halide
Hydrocarbon；As organic chemicals nX>When 0, this organic chemicals is halogenated alkane, is the 5th class organic chemicals；As organic chemicals nX
When=0, this organic chemicals is excluded；
It is as follows that this method is applicable in organic chemicals：
1. unazotized organic chemicals
2. arene chemicals：It is substitution functional group with hydroxyl or carboxyl or halogen；
3. alkanes chemicals：It is substitution functional group with hydroxyl or carboxyl or sulfonic group or sulfinic acid base or halogen；
(3) structure and characterization of Quantitative Prediction Model
It is defined as with the ability for taking the relative effect gesture RP characterization TDCs and TH of logarithm to compete hTTR binding sites, RP when modeling：
Wherein：IC50(T4) and IC50(TDCs) thyroxine T is respectively represented4With the half competitive effect concentration nM of TDCs；logRP
Value is bigger, indicates that the ability of organic chemicals and TH competition hTTR binding sites is stronger；
Inactive organic chemicals interference activity is set as to the IC of 625000nM, TH and hTTR effect50(T4) value be 61nM,
Obtain inactive chemicals relative effect gesture logRP=-4.011；
1. calculating molecular descriptor
First, optimize organic chemicals molecular structure, the organic chemicals molecular structure based on optimization calculates each organic chemistry
4885 Dragon descriptors of product；Descriptor is pre-processed according to following principle：(1) removal has the descriptor of missing values；
(2) two descriptor correlations are more than 0.99 descriptor, the big descriptor of removal standard deviation；
2. according to the classification results of step (2), aromatics and the organic organic chemicals of alkanes are constructed to hTTR disturbing effects
Prediction model：Wherein, aromatics organic chemicals prediction model includes 75 organic chemicals, training set and verification collection difference
For 61 and 14；Alkanes organic chemicals prediction model includes 33 organic chemicals, and training set and verification collection are respectively
24 and 9；Aromatics and the organic organic chemicals of alkanes are built using stepwise multiple linear regression method to interfere hTTR
The prediction model of effect；
3. prediction model expression formula：
Aromatics organic chemicals prediction model expression formula is：
LogRP=-3.181+2.515nArOH-8.990×10-1CIC3+3.463Eig15_EA(dm)+2.723×10-1H7m+
6.901×10-1RTs+ (2)
Wherein, nArOHRefer to the number of phenolic hydroxyl group in molecule, CIC3 is molecular information index, and Eig15_EA (dm) is dipole moment weighting
Characteristic value, H7m be molecular mass weighting H autocorrelation exponents, RTs+ be I-state weighting R indexes；
Alkanes organic chemicals prediction model expression formula is：
LogRP=-4.279+3.891 × 10-2H2s–1.961×10-1Mor07m
+5.476×10R8v+ (3)
Wherein, H2s is the H autocorrelation exponents of I-state weightings, and Mor07m is the 3D-MoRSE descriptors of molecular mass weighting,
R8v+ refers to the R autocorrelation exponents of second order molecular susceptibility weighting；
4. using the related coefficient square R between experiment value and predicted value2, remove a method cross validation coefficient Q2 Training set, external certificate
The related coefficient Q of collection2 Verification collectionWith the goodness of fit, robustness and the predictive ability of root-mean-square error RMSE evaluation models；
The characterization result of aromatics organic chemicals prediction model：Related coefficient between the experiment value and predicted value of training set is flat
Square R2 Training set=0.899, the root-mean-square error RMSE of training setTraining set=0.662, Q2 Training set=0.863, it is preferable to show that model has
The goodness of fit and robustness；The related coefficient Q of external certificate collection2 Verification collection=0.874, R2 Verification collection=0.879, external certificate collection
Root-mean-square error RMSEVerification collection=0.734, show that model has preferable predictive ability；
The characterization result of alkanes organic chemicals prediction model：R2 Training set=0.961, RMSETraining set=0.217, Q2 Training set=
0.940, show that model has the preferable goodness of fit and robustness；Q2 Verification collection=0.932, R2 Verification collection=0.950, RMSEVerification collection=
0.264, show that model has preferable predictive ability；
5. using the application domain of Williams figure characterization models：Williams figures are by residual and the expression of lever value, aromatics
The application domain of organic chemicals prediction model is：Lever value is less than 0.3；The application domain of alkanes organic chemicals prediction model
For：Lever value is less than 0.5；
(4) people's transthyretin chaff interferent virtual screening method
1) according to organic chemicals molecular structure group judge unknown organic chemicals whether screening technique application domain range
It is interior, if unknown organic chemicals are being classified based on above-mentioned ten groups；If not existing, does not have to the method and carry out in advance
It surveys；
2) according to unknown organic chemicals classification results, suitable prediction model is selected；Requirement based on prediction model calculates not
Know the molecular descriptor of organic chemicals, and calculates the lever value of unknown organic chemicals according to molecular descriptor, it is more unknown
Whether the lever value of organic chemicals is within the scope of the application domain of model；If unknown organic chemicals are in the application domain range of model
Interior, then the model according to selection calculates logRP value of the unknown organic chemicals to hTTR；If unknown organic chemicals are not in model
Application domain within the scope of, then predicted without this model；
3) judge whether unknown organic chemicals there is interference hTTR to transport the ability of TH and interfere energy according to the logRP values of prediction
The power of power；
The criterion of interference performance is as follows：
High interference activity：logRP≥-1.00；
Moderate interference activity：-2.00≤logRP<-1.00；
Low interference activity：-4.011≤logRP<-2.00；
Noiseless activity：logRP<-4.011.
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