CN101059520A - Organic ER affinity quick screening and forecast method based on receptor binding mode - Google Patents
Organic ER affinity quick screening and forecast method based on receptor binding mode Download PDFInfo
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Abstract
The invention discloses a quick selecting predicting method of organic ER affinity force based on acceptor combine mode, which builds QSAR judge model and predict model according to the acceptor combine modes as prior ER affinity force data pollutant, acceptor combine energy, hydrogen bond function mode, acceptor function point reach hardness or the like, and the affinity index, to be applied into the ER affinity force judgment and predication of the compound with unknown affinity force. The invention can select and predict the compounds with different structures in wide active index ranges, to predict the suspected EDCs and hormone acceptor affinity force, with low cost, simple operation, saved time, and high predict ability as 80%, and significant support on the environment management and ecology risk evaluation.
Description
Technical field
The present invention relates to bioactive screening of the suspicious incretion interferent of environment and Forecasting Methodology, be based on suspicious environment incretion interferent estrogen receptor (estrogen receptor, ER) the affinity screening and the Forecasting Methodology of receptors bind pattern specifically.
Background technology
Environment incretion interferent (endocrine disrupting chemicals, EDCs) be meant generation, release, metabolism, combination, drainage, the interactive exogenous material of keeping homeostasis in the interference biosome and regulating hormone in the growth course, also be Environmental Hormone/hormone.EDCs has just obtained people's attention to the wild animal and the mankind's harm as far back as the nineties in last century.EPA listed 60 kinds of incretion interferents in 1996.World Wildlife Fund listed 68 kinds in 1997.Japan in 1998 has carried out the incretion interferent generaI investigation in the water environment in China and has announced 75 kinds of incretion interferents in 1999.Present confirmed environment incretion interferent surpasses 100 kinds, and wherein great majority belong to persistent organism, and pollution range is wide in environment, influence is big, timeliness is long, the serious human survival that threatening.EDCs has become another serious global environmental hazard problem after greenhouse effect global warming and depletion of the ozone layer, belongs to third generation environmental contaminants, has become the hot fields of current international environmental science research about the research of EDCs.
In view of a large amount of environmental contaminants are potential environmental hormone class materials, a large amount of compounds are screened and screen is the basis of further investigation EDCs, so the triage techniques research of EDCs is paid much attention in countries in the world.1996; USEPA (EPA) is under the indication of Congress and " Federal Advisory Council's method "; set up the environment incretion interferent screening and the testing consultants council (EDSTAC), main task is to formulate screening and authentication method, the endocrine interferon activity of thoroughly evaluating EDCs.EDSTAC has recommended to screen the endocrine interferon activity with the test environment pollutant by the layer-stepping screening system that nearly kind more than 20 exsomatizes and the live body method of testing is formed.Because pollutant kind is various in the environment, because of financial resources, manpower and time are limit, all adopt so many terminal tests system, rely on laboratory work merely and screen, obviously be unpractical, therefore press for the non-experimental screening and assessment method of development at present, screen at first fast for environmental contaminants, carry out DCO detailed checkout and research on this basis again.Active relevant (the Quantitative StructureActivity Relationship of D-M (Determiner-Measure) construction, QSAR) technology can be erected bridge between EDCs structure and its endocrine interferon activity, make that solving this difficult problem becomes possible (Wang Liansheng, Han Shuo goes against. the D-M (Determiner-Measure) construction-activity of the organic contaminant .1993 that is correlated with, Beijing: the China Environmental Science Press).The QSAR method is not subjected to the restriction of experiment condition and testing tool, adopt various chemistries and data mining technology to study biologically active with predictive compound, thereby in the face of compound quantitatively the time, having particularly evident advantage, QSAR is just showing unique charm aspect EDCs screening and the risk assessment.
EDCs effect inherent mechanism mainly contains following several: 1. directly combine with acceptor; With biosome internal hormone competition target cell on acceptor; 3. some incretion interferent can produce similar estrogenic effect, and is but irrelevant with the signal pipeline of estrogen receptor; 4. influence the regulating and controlling effect of internal system and other system; 5. influence acceptor quantity; 6. influence synthesizing, store, discharge, transport and discharging of hormone.Wherein, environmental contaminants are to combine with hormone receptor with the similar form of endogenous hormone, the conformation of acceptor is changed, form the ligand-receptor compound, compound is attached on the hormone response element (HRE) of cell nuclear dna in conjunction with the territory again, induce or suppress transcribing of the relevant target gene of regulating the cell g and D, thereby a series of hormonal dependent physiological and biochemical procedures are impacted, the receptor-mediated pattern that produces various environmental hormone effects especially receives publicity.EDCs can induce or suppress the multiple physiological effect relevant with hormone with the target recipient combination, and wherein, estrogen receptor participates in a lot of important physical processes of mediation, and estrogen receptor affinity index is to characterize the bioactive important parameter of suspicious EDCs,
J. wait summarized environmental chemicals and nuclear receptor effect, effect and relevant testing in vitro recent progress in experimental study (
J., Hilscherov á K., Bl á ha L., et al.Environmental xenobiotics and nuclear receptors-Interactions, effects and in vitroassessment.Toxicology in Vitro, 2006,20:18-37.).
Along with computer science and molecular biological progress, at present the QSAR method also develops into and can set up suitable three-dimensional QSAR model (3D-QSAR) according to compound three dimensions conformation information parameter and activity index from traditional two dimensional model prediction, mainly can be divided into 3D-QSAR based on the part space structure (as relatively molecular field (CoMFA)/comparison molecular mimicry sex index (CoMSIA), holographic elements QSAR (HQSAR) etc.) and based on the 3D-QSAR (comprise and calculate the receptors bind free energy and simulate part-receptor acting pattern etc.) of acceptor three-dimensional structure.Wherein space structure information and its index of biological activity of extraction compounds such as CoMFA, CoMSIA, HQSAR are analyzed, and be therefore better to the close compound prediction effect of a series of structures, can inquire into the influence of different pharmacophore structures to compound activity.Set up the forecast model of 30 kinds of derivatives of estradiol ER affinities as usefulness HQSAR methods such as Cui Shihai, the cross validation related coefficient be 0.897 (Cui Shihai, Liu Shushen, Wang Xiaodong etc. the HQSAR research of derivatives of estradiol. Science Bulletin, 2003,48 (3): 239-242.).But, have the theory hypothesis of a priori based on the QSAR method of part, promptly compound put same action site combination with target and binding mode identical.If a collection of compound is different with the target point mode of action, then the robustness of gained QSAR model and predictive ability all can be a greater impact; Just must carry out the classification of chemical constitution if want the goodness of fit that improves method to the organic contaminant of being studied.Utilize CoMFA and HQSAR method to set up the prediction and evaluation model of the estrogen receptor affinity index of 130 kinds of EDCs as Shi L.M. etc.Shi L.M. etc. at first classifies to compound by structure, and 130 kinds of compounds are divided into steroids, diethylstilbestrol derivant and phytoestrogen, DDT class and bisphenol-a derivative, PCBs, alkyl phenol and alkoxy phenol, miscellany compound totally 6 classes; Then each class is all carried out superimposedly by the apokoinou construction of uniqueness respectively, carry out CoMFA research; At last all predicted data are gathered, and the related coefficient between experiment affinity index is 0.91; The related coefficient of HQSAR method then be 0.76 (Shi L.M., Fang H., Tong W., et al.QSAR models using a large diverse set of estrogens.J.Chem.Inf.Comput.Sci., 2001,41:186-195.).Fang H. etc. have carried out studying based on the structure-activity relation of ligand structure to 230 kinds of compounds according to the ER affinity, analyzed the influence of different substituents to the ER affinity, utilize the pharmacophore searching method to seek the common structure of ER part, 5 essential standard (Fang H. that a kind of compound will possess estrogen active have been provided from the ligand structure angle, Tong W., Shi L.M., et al.Structure-ActivityRelationships for a large diverse set of natural, synthetic, and environmental estrogens.Chem.Res.Toxicol., 2001,14:280-294.).Hong H. etc. judge according to two kinds of refusals, the complicated conjunctive model of a kind of tree shape model and three kinds of construction standards judges 58, can 000 kind of compound combine with ER, model is mainly used in judges whether a kind of compound is the ER part, false determination ratio is 19.2% (Hong H., Tong W., Fang H., et al.Prediction of estrogen receptor binding for 58,000 chemicals using anintegrated system of a tree-based model with structural alerts.Environmental HealthPerspectives, 2002,110 (1): 29-36.), Hong H. points out that simultaneously inconsistent rate has also reached 15% between two kinds of experiment test methods.The structured descriptor that above method all is based on organic contaminant is differentiated the acceptor affinity power of itself and hormone receptor effect power.
Brzozowski etc. to some compounds and biosome inner estrogen acceptor in conjunction with after the compound cocrystallization, study its crystal structure and find that there are significant difference in the binding mode and the action site of dissimilar compounds and estrogen receptor activity pocket, and on Nature, reported achievement in research (Brzozowski, A.M., Pike, A.C., Dauter, Z., et al.Molecular basis of agonism and antagonism in the estrogenreceptor.Nature, 1997,389,753-758.).As seen, in the differentiation screening of big to structural span, miscellaneous organic contaminant hormone receptor affinity ability, there is certain limitation based on the QSAR method of part, is difficult to solve the problem that compound and target are put different action sites combinations or combined with different binding modes with same action site.And not only consider the effect of three-dimensional structure in its receptor of organic contaminant based on the 3D-QSAR method of acceptor three-dimensional structure, can also Simulation evaluation biomacromolecule structure to the influence of pollutant-hormone receptor combination, can carry out simulation screening to a certain extent, and the exploration of suspicious EDCs endocrine interference mechanism is had directive significance based on the ligand-receptor binding mode.Generally, pollutant and the effect of biological target punctuate mainly be subjected to its transmission be transported to target point complexity and with the binding mode of target point with strong and weak relevant.Hydrophobicity index logP is the important parameter that characterizes transmission transhipment in organic contaminant biological cell, tissue, the organ, and organic contaminant mainly combines by nonbonding effects such as hydrogen bond action, Van der Waals force, hydrophobic effects with the estrogen receptor activity pocket.Hydrogen bond action is the main effect that makes that compound system is stable, whether pollutant can form hydrogen bond and power thereof etc. with the acceptor specific site has material impact to the affinity size of compound and estrogen receptor molecule, therefore the binding mode of different compounds of research and analysis and estrogen receptor activity pocket can help us to understand the interactional micromechanism of pollutant-estrogen receptor from molecular level, gives the fast and reasonable screening to organic contaminant-estrogen receptor affinity.
Sars coronavirus 3CL proteinase 3 d structure model and anti-SARS medicine (number of patent application: 03129071.X; Publication number: CN 1472336A; The open date: on February 4th, 2004; Inventor: Shen Jianhua, Jiang Hualiang, Shen Xu etc.) by the three-dimensional structure of molecular simulation acquisition SARS-CoV virus 3CL albumen, with the existing drug data base of molecular docking virtual screening search, seek anti-SARS medicine as target.Estrogen activity of environmental organic contaminant based is in the rapid screening method (number of patent application: 200610097362 of molecular structure; Publication number: 1963523; The open date: on May 16th, 2007; Inventor: Xiao Qianfen, Wang Xiaodong, Liu Shu is dark etc.) disclose a kind of estrogen affinity ability based on ligand structure (being the organic contaminant structure) and differentiated screening technique, specifically be at first compound to be divided into 8 classes by structure, utilize the structural information parameter of Dragon computed in software compound molecule, and compound classified, utilize discriminant function and the classification center of gravity of QASAR modelling, but whether the preliminary judgement compound is environmental estrogens based on Euclidean distance.
Literature search is the result show, before the present invention finishes, also do not find based on the receptors bind pattern suspicious EDCs and estrogen receptor affinity to be differentiated fast the report of screening.
Summary of the invention
1. invent the technical matters that will solve
The chemical quantity that enters environment is numerous, and pass in time and be increase trend, wherein comprise a lot of suspicious incretion interferents, about the screening of these compounds with determine it is that the control incretion interferent pollutes, ensure the prerequisite of human health, it also is urgent problem in the incretion interferent research, each compound is carried out biological chemistry and the huge manpower of toxicological experiment needs, material resources, financial resources, present existing screening and Forecasting Methodology are subject to obtaining and describing of the structural information of compound own, and be limited than the predictive ability of large compound hormone affinity to textural difference.The objective of the invention is to provide a kind of and judge and the method for prediction chemicals acceptor affinity, can judge the screening technique of environmental chemicals estrogen receptor affinity based on organic contaminant and hormone receptor target point binding mode quick, easy, economically based on the hormone receptor structural information.
2. technical scheme
Principle of the present invention is according to existing ER affinity data contamination thing and receptors bind energy, hydrogen bond action pattern and arrives receptors bind pattern such as receptor acting site complexity and the relation of affinity index and set up QSAR discrimination model and forecast model based on receptor structure, and applies it to a kind of method that the ER affinity differentiation of ER affinity unknown compound is predicted.
The technical scheme that adopts is as follows:
Based on the organism ER affinity rapid screening Forecasting Methodology of receptors bind pattern, its step comprises:
(1), the organic contaminant of known estrogen receptor affinity is divided three classes or four classes by itself and estrogen receptor affinity power according to compound relative affinity size; Every class is randomly drawed a kind of as prediction group at least, and all the other form the training group.The relative affinity index adopts logRBA, and (RBA is a relative affinity, be the ratio of compound affinity and estradiol affinity, the relative affinity of estradiol is made as 100), logRBA＜-3,-3≤logRBA＜0, logRBA 〉=0 correspond respectively to extremely weak ER affinity, weak ER affinity, strong ER affinity; The situation of logRBA 〉=0 o'clock also can be further divided into two classes, i.e. 0≤logRBA＜1 and logRBA 〉=1, corresponding medium tenacity affinity, high affinity respectively;
(2) measure the species and the hypotype of the acceptor that uses according to having estrogen receptor affinity data experiment, the estrogen receptor crystal structure of selecting to combine with dissimilar activators and antagonist from Protein Data Bank (PDB) is set up the ER model, the selection of action site is to adopt SiteID (SYBYL7.0, TriposInc.) the equimolecular analogy method is sought the macromolecular active pocket of acceptor, selects the active residue interior residue composition substrate binding pocket of certain limit on every side.Under the estrogen receptor three-dimensional structure condition of unknown that experiment is used, the receptor structure mould is built can be according to methods such as homology adopt that point mutation, homology mould are built.When unknown ER and known ER homology were higher than 90%, ligand binding domain only had several residue differences, and its protein folding pattern is basic identical, adopted the method for point mutation to replace minority to the residue that folding pattern does not play a decisive role, and set up unknown structure ER model; For the unknown ER of homology difference, use target sequence from ncbi database (National Center for Biotechnology Infomation, http://www.ncbi.nih.gov), the method that adopts the homology mould to build makes up receptor model.
(3) be built with organic pollutants spatial configuration of molecules and carry out configuration and energy-optimised, adopt molecular docking to calculate hydrogen bond action patterns such as the site that combines free energy and formation hydrogen bond of suspicious environment incretion interferent and hormone receptor active pocket and quantity.Specifically: make up organic constitution, it is energy-optimised to use the Tripos field of force that all compounds are carried out, and electric charge is chosen as Gasteiger-H ü ckel electric charge, and the energy convergence is 0.05kcal/mol, and maximum iteration time is set to 1000 times.Use FlexX molecular docking method that compound and estrogen receptor activity pocket are carried out molecular docking, calculate receptors bind free energy E
Binding, butt joint failure E
BindingAssignment is 20.Hydrogen bond action number (the N of computerized compound and active pocket residue
HB), each indieating variable H represents whether Key residues, water of crystallization etc. form hydrogen bond in compound and the ER active pocket, forms hydrogen bond action, corresponding indieating variable is made as 1, otherwise is made as 0;
(4) when the molecular structure type more for a long time, have significant difference because of the structure difference causes its transmission transport properties in cell, tissue etc., add organic contaminant hydrophobicity parameter l ogP and characterize the complexity that its transmission is transported to target point;
(5) plant estrogen (phytoestrogens) is the more special ER part of a class, has special binding pattern with ER, when low concentration, show weak estrogen active, and after concentration raises, show the antiestrogenic ability, as seen itself and estrogen receptor have special binding pattern, then increasing indieating variable X1 in screening indicates and differentiation (there is such material in 1 expression, and 0 expression is not);
(6) combine free energy E to characterize logP, the description compound that the organic contaminant transmission is transported to the complexity of target point with the indieating variable H and the ER of ER target spot hydrogen bond action pattern
Binding, compound and ER form the number N of hydrogen bond
HB, and indieating variable X1 be independent variable, adopt discriminant analysis method to establish the discriminant function Y of organic pollutants and estrogen receptor affinity power grade;
(7), set up 3-D quantitative structure effect model (form is logRBA=aE with the free energy that combines of estrogen receptor activity pocket according to it if there be an action site organic contaminant close with the hydrogen bond action pattern
Binding+ b), the similar but acceptor affinity of acceptor affinity types of unknown pollutants of predict;
(8) adopt the discrimination model and the quantitative forecast model that obtain can carry out rapid screening to the estrogen receptor affinity of affinity types of unknown pollutants, differentiate and prediction.
(Blair R.M. such as Blair R.M., Fang H., Branham W.S., et al.The estrogen receptorrelative binding affinities of 188 natural and xenochemicals:structural diversity ofligands.Toxicological Sciences, 2000,54:138-153.) according to the scope of relative affinity index logRBA the ER part is divided into a little less than, in, strong three classes, two separations of corresponding logRBA are respectively-2 and 0, be that ten thousand/time that compd E R affinity is lower than estradiol is weak ER part, estradiol affinity ten thousand/and one of percentage between be the ER part of medium tenacity, affinity greater than the estradiol affinity centesimal be strong ER part.Hong H. etc. thinks that the logRBA of compound is lower than at-4.5 o'clock and can not effectively combines (Hong H. with ER, Tong W., Fang H., et al.Prediction of estrogen receptor bindingfor 58,000 chemicals using an integrated system of a tree-based model with structuralalerts.Environmental Health Perspectives, 2002,110 (1): 29-36.).Matthews etc. think that then logRBA is lower than-3 compound and can not effectively combines (Matthews J. with ER in the experimental concentration scope, Celius T., Halgren R., et al.Differential estrogen receptor binding of estrogenicsubstances:a species comparison.Journal of Steroid Biochemistry ﹠amp; MolecularBiology, 2000,74:223-234.).Therefore, compound and acceptor affinity are in 10 of its native ligand affinity
-5When doubly following for affinity compound a little less than extremely, greater than 10
-5Doubly and less than 10
-2Times the time be weak affinity compound, greater than 10
-2Times the time be the strong affinity compound, this wherein can be divided into two classes again, greater than 10
-2Doubly less than 10
-1The time be medium tenacity affinity compound, greater than 10
-1Times the time be converted to the relative affinity index for the high affinity compound, then correspond respectively to logRBA＜-3 ,-3≤logRBA＜0, logRBA 〉=0, wherein logRBA 〉=0 is divided into 0≤logRBA＜1 and logRBA 〉=1 liang class again.Target compound according to relative affinity index height, medium tenacity, rank classification such as weak, extremely weak or strong, weak, extremely weak, is divided three classes at least.Every class is randomly drawed a kind of as prediction group at least, and all the other form the training group.Prediction group mainly is whether the model that check is built has reached its intended purposes, so 1～3 compound that respectively stays of different activities gets final product in the check group in the general same compounds.
Above-mentioned acceptor specy comprises the various species that can mediate biosome inner estrogen response and the estrogen receptor of hypotype.Measure the species and the hypotype of the acceptor that uses according to existing estrogen receptor affinity data experiment, the estrogen receptor crystal structure of selecting to combine with dissimilar activators and antagonist from Protein Data Bank (PDB) is set up the ER model, the selection of action site is to adopt SiteID (SYBYL7.0, Tripos Inc.) the equimolecular analogy method is sought the macromolecular active pocket of acceptor, selects the active residue interior residue composition substrate binding pocket of certain limit on every side.Under the estrogen receptor three-dimensional structure condition of unknown that experiment is used, the receptor structure mould is built can be according to methods such as homology adopt that point mutation, homology mould are built.When unknown ER and known ER homology were higher than 90%, ligand binding domain only had several residue differences, and its protein folding pattern is basic identical, adopted the method for point mutation to replace minority to the residue that folding pattern does not play a decisive role, and set up unknown structure ER model; Unknown ER for the homology difference, use is from ncbi database (National Center forBiotechnology Infomation, http://www.ncbi.nih.gov) target sequence, the method that adopts homology moulds such as ESyPred3D, Spark2 to build makes up receptor model.Homology as mER α and hER α is the highest, only has a few residue to change in the LBD district, in the residue of composition active pocket a residue difference is only arranged, and can consider to adopt point mutation process to set up mER α receptor model.And the homology of lizard and rainbow trout ER and hER α is less than 90%, thereby can utilize the webservers such as ESyPred3D, Spark2 to make up both ER homology models, utilizes PROCHECK that the receptor model that makes up is carried out the rationality evaluation.
The above-mentioned organic energy-optimised use Tripos field of force, electric charge is chosen as Gasteiger-H ü ckel electric charge, and the energy convergence is 0.05kcal/mol, and maximum iteration time is set to 1000 times.Use FlexX molecular docking method that compound and estrogen receptor activity pocket are carried out molecular docking, calculate the receptors bind free energy.Hydrogen bond action number (the N of computerized compound and active pocket residue
HB).Each indieating variable H represents whether Key residues, water of crystallization etc. form hydrogen bond in compound and the ER active pocket: form hydrogen bond action, corresponding indieating variable is made as 1, otherwise is made as 0; As H
Glu353, H
Leu387, H
Gly521, H
His524, H
Leu346, H
Water, H
OtherBe respectively to judge whether compound and ER active pocket interior residue Glu353, Leu387, Gly521, His524, Leu346, water of crystallization and other site form the indieating variable of hydrogen bond action, if hydrogen bond action is arranged, corresponding indieating variable is made as 1, otherwise is made as 0.
When the molecular structure type more for a long time, can adopt computing method or methods acquisition organic contaminant hydrophobicity parameter l ogP such as data base querying, literature search such as fragment constant method, description characterizes its transmission and is transported to the complexity of target point and the relation of reconditioning and effective dose because of the structure difference causes its transmission transport features in cell, tissue etc.Comprised that the hydrophobicity supplemental characteristic of a large amount of compounds can obtain easily in document and the database at present, need consider this factor during to the numerous a series of compound of complex structure, kind, but should adopt the parameter value that comes from a kind of experiment test or computing method to guarantee the consistance of data a collection of compound.
Some can activate and organic contaminant that can the inhibitory hormone activity is controlled with amino acid residue around combining of hormone receptor may not only be subjected to its binding site, and is also relevant with the transformation of the whole conformation of acceptor.Plant estrogen (phytoestrogens) is exactly the more special ER part of a class, has special binding pattern with ER, when low concentration, show weak estrogen active, and after concentration raises, show the antiestrogenic ability, as seen itself and estrogen receptor have special binding pattern, this method is used indieating variable X1 to indicate in screening and is distinguished (there is such material in 1 expression, and 0 expression is not).
The discrimination model feature of the strong and weak grade of above-mentioned organic contaminant and hormone receptor affinity is: the hydrogen bond action pattern between analysis of compounds and active pocket amino acid residue, characterize the complexity that the organic contaminant transmission is transported to target point with logP, characterize the hydrogen bond that is subjected to body characteristics target point with indieating variable H and form situation (1 this site of expression and pollutant formation hydrogen bond, 0 expression is not), N is set
HBVariable is to hydrogen bond number counting, the binding energy E of computerized compound and estrogen receptor
Binding, butt joint failure E
BindingAssignment is 20, represents to have or not plant estrogen with indieating variable X1.Adopt the mahalanobis distance method to set up the discriminant function Y (Y=a that pollutant-estrogen receptor affinity power is differentiated
1LogP+a
1E
Binding+ a
3N
HB+ a
4X
1+ a
5H ...), mahalanobis distance method (Mahalanobis distance) has the advantages such as interference that are not subjected to each variable dimension to influence, can get rid of correlativity between variable.
For the action site organic contaminant close with the hydrogen bond action pattern, set up the 3-D quantitative structure according to itself and the high correlation that combines free energy and acceptor affinity index of estrogen receptor activity pocket and imitate the model prediction similar but the acceptor affinity of acceptor affinity types of unknown pollutants, form is logRBA=aE
Binding+ b.The discrimination model of above-mentioned acquisition and quantitative forecast model can carry out rapid screening to the hormone receptor affinity of affinity types of unknown pollutants, differentiate and prediction; The receptor acting site of adopting said method to obtain can be used for virtual screening and searches for existing chemicals database, obtains the suspicious organic contaminant of high hormone receptor affinity, preferentially experimentizes to measure and research.
3. beneficial effect
Adopt the power of the inventive method screening prediction suspicious EDCs of environment and hormone receptor affinity, all can differentiate screening and prediction to the different compound of the structure of wide range activity index, method is with low cost, easy to be reliable, can save great amount of manpower and material resources, financial resources, the consensus forecast ability reaches more than 80%, and the environmental management and the ecological risk assessment that predict the outcome to respective compound have important directive significance.
Description of drawings
Fig. 1 is the hydrogen bond action synoptic diagram of compound dienestrol (dienestrol) and ER alpha active pocket;
The Ramachandran figure that Fig. 2 estimates for the protein structure rationality;
Fig. 3 is yellow (alkane) ketone, isoflavonoid linear relationship chart in conjunction with free energy and affinity index;
Fig. 4 is the calculated value of compound logP and the graph of a relation of experiment value.
Embodiment
Further specify the present invention by the following examples in conjunction with the accompanying drawings
Embodiment 1:
Adopt the inventive method to handle one group of ER part and non-ER part (Matthews J., Celius T., Halgren R., et al.Differential estrogen receptor binding of estrogenic substances:aspecies comparison.Journal of Steroid Biochemistry ﹠amp; Molecular Biology, 2000,74:223-234.) totally 34 kinds of compounds.
Principle of classification: compound is divided into 4 classes: 1～logRBA＜-3 by the logRBA value, 2～-3≤logRBA＜0,3～0≤logRBA＜1,4～logRBA＞1, respectively the extremely weak ER affinity of correspondence, weak ER affinity, medium tenacity ER affinity, high ER affinity are four types, compare with the acceptor affinity of estradiol ,-3,0,1 three corresponding respectively affinity multiples of interval separation be 100,000 of estradiol/, one of percentage is with 1/10th.Set up the formwork erection type from wherein extracting 30 kinds of compounds as training, remain 4 kinds of compounds and verify as test group (corresponding to 4 types).
Receptor structure: selection combines the crystal structure (PDB is encoded to 1ERE) of the human estrogen receptor alpha hypotype of estradiol and sets up receptor model, utilizes SiteID (SYBYL7.0, Tripos Inc.) to seek the active pocket of acceptor molecule ligand binding domain.
Compound treatment and molecular docking: make up compound structure, use the Tripos field of force to carry out energy-optimised to all compounds, electric charge is chosen as Gasteiger-H ü ckel electric charge, and the energy convergence is 0.05kcal/mol, and maximum iteration time is set to 1000 times.Use FlexX that compound and receptor active pocket are carried out flexible docking, calculate the receptors bind free energy, when compound docks failure with acceptor molecule, E
BindingIt is 20 that value is composed.Hydrogen bond action number (the N of computerized compound and active pocket residue
HB), use indieating variable H
Glu353, H
Leu387, H
Gly521, H
His524, H
Leu346, H
Water, H
OtherThe hydrogen bond action of judging residue Glu353, Leu387, Gly521, His524, Leu346, water of crystallization and other site in compound and the pocket respectively has or not, if hydrogen bond action is arranged, corresponding indieating variable is made as 1, otherwise is made as 0.
Hydrophobicity parameter: do not need to add the hydrophobicity parameter in this example and characterize the complexity that its transmission is transported to target point.
Have plant estrogen in this example, plant estrogen is the ER part that a class has the special combination pattern, shows weak estrogen active when low concentration, and shows the antiestrogenic ability after concentration raises, and therefore sets up an indieating variable X
1, if compound is a plant estrogen, then this value tax is 1, is 0 otherwise compose.
Adopt the N of compound
HB, X
1, E
BindingAnd H
Glu353, H
Leu387, H
Gly521, H
His524, H
Leu346, H
Water, H
OtherCarry out progressively discriminatory analysis Deng hydrogen bond action mode parameter and logRBA classification situation based on the mahalanobis distance method.Advise following discriminant function:
Y
1＝0.407X
1-7.418H
Leu387+0.285H
Leu346+1.902N
HB-2.000
Y
1Differentiate center of gravity and be respectively 1～-1.789,2～2.554,3～-0.098,4～1.851;
Y
2＝4.702X
1-4.251H
Leu387+3.920H
Leu346-0.484N
HB+0.097
Y
2Differentiate center of gravity and be respectively 1～0.126,2～2.339,3～-0.387,4～-1.098
Y
3＝0.311X1+2.441H
Leu387+0.543H
Leu346+0.045N
HB-0.392
Y
3Differentiate center of gravity and be respectively 1～0.012,2～0.001,3～-0.346,4～0.015
From the discriminant function cumulative percentage as can be seen, Y
1Judgement is very strong, accounts for 76.4%, Y
2Certain judgement is also arranged, account for 23.5%, and Y
3Almost inoperative in differentiation, only account for 0.1%.It is 87.1% that equation is always declared ability.
Modelling verification: use Y
1And Y
24 compounds of test group are verified that accuracy is 87.5%.
Embodiment 2:
Adopt the inventive method to handle toxicologic study center (the national center fortoxicological research of U.S. FDA country, NCTR) 232 kinds of compounds in the ER affinity database (Estrogen receptor bindingdataset, www.fda.gov/nctr/science/centers/toxicoinformatics/edkb/ index.htm).
Principle of classification: compound and ER affinity index can be divided into 3 classes: 1～logRBA＜-3 for having the compound of extremely weak ER affinity, and 2～-3≤logRBA＜0 is for having weak ER affinity, and 3～logRBA 〉=0 is for having the compound of ER strong affinity.From 188 kinds of non-plant estrogen, extract 180 compounds and set up the formwork erection type as training, comprising each 111,45,24 of 1,2,3 compounds, plant the rerum natura estrogen from 44 kinds and to extract 40 kinds, comprise that 1,2,3 compounds are respectively 16,22,2 as the training group models.All the other 12 kinds of compounds are verified model as the test group.
Receptor structure: the affinity index of compound comes from the rat uterus endochylema among the ER competition of estradiol in conjunction with IC in the database
50And the document result shows significant correlation between rat uterus ER affinity and human ER α affinity index, and compound quantity is a lot, structure is different, comprise polytypes such as activator, antagonist and selectivity ER part, therefore the 6 kinds of ER alpha-crystal structural models (the PDB numbering is respectively 1ERE, 1ERR, 1R5K, 3ERT, 1a52,1L2I) that combine dissimilar compounds are adopted in the foundation of receptor model, seek active pocket with SiteID (SYBYL7.0, Tripos Inc.)
Compound treatment and molecular docking: make up compound structure, use the Tripos field of force to carry out energy-optimised to all compounds, electric charge is chosen as Gasteiger-H ü ckel electric charge, and the energy convergence is 0.05kcal/mol, and maximum iteration time is set to 1000 times.Use FlexX respectively compound to be carried out flexible docking with different receptor active pockets, select in conjunction with the binding pattern of the minimum a kind of pattern of free energy index as compound and ER, calculating receptors bind free energy, compound docks with acceptor molecule when failing, E
BindingIt is 20 that value is composed.Hydrogen bond action number (the N of computerized compound and active pocket residue
HB), use indieating variable H
Glu353, H
Leu387, H
Gly521, H
His524, H
Leu346, H
Water, H
OtherThe hydrogen bond action of judging residue Glu353, Leu387, Gly521, His524, Leu346, water of crystallization and other site in compound and the pocket respectively has or not, if hydrogen bond action is arranged, corresponding indieating variable is made as 1, otherwise is made as 0.
Because compound quantity is more, because of causing its transmission transport properties in cell, tissue etc., the structure difference has significant difference, ogP characterizes the complexity that its transmission is transported to target point with compound hydrophobicity parameter l, is added in the decision rule as a numerical variable.The logP value of compound is from the NCTR database.
Have plant estrogen in this example, plant estrogen is the ER part that a class has the special combination pattern, therefore sets up an indieating variable X
1, if compound is a plant estrogen, then this value tax is 1, is 0 otherwise compose.
Adopt logP, the N of compound
HB, X
1, E
BindingAnd H
Glu353, H
Leu387, H
Gly521, H
His524, H
Leu346, H
Water, H
OtherCarry out progressively discriminatory analysis Deng hydrogen bond action mode parameter and logRBA classification situation based on the mahalanobis distance method.Advise following discriminant function:
Y
1＝-0.773X
1-0.007E
binding+0.261logP+1.647H
Glu353-0.573H
Gly521+0.435H
other+0.786N
HB-2.626，
Y
1Differentiate center of gravity and be respectively 1～-0.954,2～0.673,3～2.916;
Y
2＝-2.204X
1-0.090E
binding-0.153logP+0.426H
Glu353+0.048H
Gly521+1.202H
other+0.090N
HB+1.449，
Y
2Differentiate center of gravity and be respectively 1～0.164,2～-0.542,3～0.579;
From the discriminant function cumulative percentage as can be seen, Y
1Judgement is very strong, accounts for 92.1%, Y
2Almost inoperative in differentiation, account for 7.9%.It is 82.1% that equation is always declared ability.
Modelling verification: 12 compounds of test group are verified, judged that total accuracy is 83.3%.
Embodiment 3:
Adopt the binding mode of the inventive method analysis of compounds and receptor active pocket.Select the dienestrol (dienestrol) in the NCTR database to dock with hER α (PDB is numbered 1ERE) active pocket, the effect synoptic diagram (accompanying drawing 1) (hydrogen bond action dots) that shows compound and acceptor pocket, the hydrogen bond action of judging residue Glu353, Leu387 in compound and the pocket, Gly521, His524, Leu346, water of crystallization (water) and other site (other) has or not, and calculating hydrogen bond number.Compound combines free energy E with pocket
BindingFor-25.1kcal/mol, show the skeleton structure of forming pocket Key residues and water of crystallization among the figure, the main zone of action violet spot matrix representation of active pocket, on the alpha-carbon atom of residue, mark residue title and sequence number, and press atomic type with this part the residue main chain of line style models show of different colours and the non-hydrogen atom on the side chain, the structure of dienestrol is with rod shape models show.Hydrogen bond action marks with dotted yellow line, and visible compound d ienestrol is positioned at active pocket central authorities, and two hydroxyl forms hydrogen bond with carboxylic end, water of crystallization and the Gly521 of Leu387 respectively, has shown the good binding ability.Therefore, according to the indieating variable assignment of method among the present invention to the various hydrogen bond actions of this compound, H
Glu353=0, H
Leu387=1, H
Gly521=1, H
His524=0, H
Leu346=0, H
Water=1, H
Other=0, the hydrogen bond number N
HB=3.
Embodiment 4:
Adopt the inventive method to handle the binding mode research of big molecule of acceptor and ligand compound, to the big molecule of acceptor that does not obtain crystal structure, reach 30% when above in the protein sequence homology, according to the theory three-dimensional spatial model of the homologous protein modelling unknown structure acceptor of existing crystal structure.This example has been set up a kind of 3 d structure model of estrogen receptor with homology mould construction method.Employed target sequence is from ncbi database (National Center for Biotechnology Infomation, http://www.ncbi.nih.gov), sequence number GI:103903, this is the estrogen receptor that a strain derives from rainbow trout (rainbow trout), form by 574 amino acid residues, when model construction, only can make up its ligand binding region (316-508).Use webserver ESyPred3D to make up rainbow trout estrogen receptor three-dimensional structure according to the three-dimensional structure (the acceptor file comes from the pdb file that PDB is numbered 1a52) of human estrogen receptor alpha hypotype.
Utilize the PROCHECK program that the albumen that makes up is carried out the rationality evaluation, consider the spatial structure information of main chain and side chain.Can analyze the dihedral angle information that is in rational position by Ramachandran figure (accompanying drawing 2), the residue that is positioned at black region is in dihedral angle zone rationally, and grey is taken second place, and the residue that is in white portion may be unreasonable.In the model that makes up, all residues are in dihedral angle zone rationally, and the G-factor is 0.14, illustrate that the main chain and the side chain character that make up all are in rational state, and the bond distance, bond angle and the public planarity that make up model are also all quite reasonable.
Embodiment 5:
Adopt the inventive method to handle the big molecule of acceptor of unknown three-dimensional structure,, can make up the unknown structure receptor model the acceptor molecule point mutation of known structure for the acceptor of sequence homology more than 90%.This example has made up mouse estrogen receptor alpha hypotype ligand binding domain with point mutation process according to the three-dimensional structure (the receptor structure file is from the acceptor file that is numbered 1a52 among the PDB) of human estrogen receptor alpha hypotype ligand binding domain, and (both sequence homologies are 97.2%, 8 residue differences are arranged) structure, point mutation is carried out in 8 positions, be respectively L306 with human estrogen receptor, I326, L327, T334, V368, T371, Q502, S527 replaces with the P310 in the mouse acceptor, M330, I331, S338, G372, N375, R506, N531 (alphabetical represented amino acid residue abbreviation, the numbering of digitized representation residue in the acceptor file), adopt the evaluation method among the embodiment 5 to show that all residues all are in reasonable zone.
Embodiment 6:
Adopt (different) yellow (alkane) ketone compounds in the NCTR database of being mentioned in the inventive method Processing Example 2, selection has 21 kinds (different) yellow (alkane) ketone compounds of affinity activity, it is carried out linear regression (accompanying drawing 3) in conjunction with free energy and relative affinity index, and regression equation is:
LogRBA＝(-0.258±0.024)E
binding-(7.051±0.450)，N＝21，R
2＝0.862，SE＝0.376，P＝0.000。
Hence one can see that (different), and yellow (alkane) ketone compounds has tangible linear relationship with the free energy that combines of ER α with its affinity index, and low more in conjunction with free energy, then the affinity of compound and ER α is high more.
Embodiment 7:
Adopt the inventive method that unknown affinity compound is differentiated, screened and predicts, in this example 21 kinds of compounds among the embodiment 6 are randomly drawed 3 kinds as unknown compound, with the residue 18 kinds of compounds carry out linear regression in conjunction with free energy and relative affinity index, new regression equation is LogRBA=(0.266 ± 0.030) E
Binding-(7.160 ± 0.551), N=18, R
2=0.833, SE=0.392, P=0.000.To the predicated error of 3 kinds of compounds in ± 0.65 scope.
Embodiment 8:
Adopt the inventive method to handle one group of compound, when the molecular structure of compounds type more for a long time, can adopt computing method or methods acquisition organic contaminant hydrophobicity parameter l ogP such as data base querying, literature search such as fragment constant method, description characterizes its transmission and is transported to the complexity of target point and the relation of reconditioning and effective dose because of the structure difference causes its transmission transport features in cell, tissue etc.This example has been randomly drawed 16 kinds in 232 kinds of compounds of NCTR database among the embodiment 3, be respectively genistein, equol, daidzein, formononetin, 4-n-octylphenol, o, p '-DDE, bis (2-ethylhexyl) phthalate, progesterone, β-testosterone, 2-hydroxy-estradiol, nonylphenol, 4-hydroxy-estradiol, moxestrol, ICI164,384,17 α-estradiol, quercetin.With the logP (accompanying drawing 4) of Chemoffice computerized compound, and with database in the value that provides relatively.Calculated value and the experiment value of 16 kinds of compound logP are returned, and regression equation is Y=(0.906 ± 0.038) X+ (0.554 ± 0.182), N=16, R
2=0.975, SE=0.336, P=0.000 illustrates that calculated value and laboratory coincide.
Claims (10)
1. organism ER affinity rapid screening Forecasting Methodology based on the receptors bind pattern may further comprise the steps:
(1), the organic contaminant of known estrogen receptor affinity is divided three classes or four classes by itself and estrogen receptor affinity power according to compound relative affinity size; Every class is randomly drawed a kind of as prediction group at least, and all the other form the training group; The relative affinity index adopts logRBA, logRBA＜-3 wherein, and-3≤logRBA＜0, logRBA 〉=0 correspond respectively to extremely weak ER affinity, weak ER affinity, strong ER affinity; The situation of logRBA 〉=0 o'clock also can be further divided into two classes, i.e. 0≤logRBA＜1 and logRBA 〉=1, corresponding medium tenacity affinity, high affinity respectively;
(2) measure the species and the hypotype of the acceptor that uses according to having estrogen receptor affinity data experiment, the estrogen receptor crystal structure of selecting to combine with dissimilar activators and antagonist from Protein Data Bank is set up the ER model, the selection of action site is to adopt the SiteID molecule simulation method to seek the macromolecular active pocket of acceptor, selects the active residue interior residue composition substrate binding pocket of certain limit on every side;
(3) be built with organic pollutants spatial configuration of molecules and carry out configuration and energy-optimised, adopt molecular docking to calculate hydrogen bond action patterns such as the site that combines free energy and formation hydrogen bond of suspicious environment incretion interferent and hormone receptor active pocket and quantity;
(4) when the molecular structure type more for a long time, have significant difference because of the structure difference causes its transmission transport properties in cell, tissue etc., add organic contaminant hydrophobicity parameter l ogP and characterize the complexity that its transmission is transported to target point;
(5) plant estrogen is the more special ER part of a class, has special binding pattern with ER, when low concentration, show weak estrogen active, and after concentration raises, show the antiestrogenic ability, as seen itself and estrogen receptor have special binding pattern, then increase indieating variable X in screening
1Indicate and differentiation;
(6) combine free energy E to characterize logP, the description compound that the organic contaminant transmission is transported to the complexity of target point with the indieating variable H and the ER of ER target spot hydrogen bond action pattern
Binding, compound and ER form the number N of hydrogen bond
HB, and indieating variable X
1Be independent variable, adopt discriminant analysis method to establish the discriminant function Y of organic pollutants and the strong and weak grade of estrogen receptor affinity;
(7), set up 3-D quantitative structure effect model: logRBA=aE with the free energy that combines of estrogen receptor activity pocket according to it if there be the action site organic contaminant close with the hydrogen bond action pattern
Binding+ b, the similar but acceptor affinity of acceptor affinity types of unknown pollutants of predict;
(8) adopt the discrimination model and the quantitative forecast model that obtain that the estrogen receptor affinity of affinity types of unknown pollutants is screened, differentiated and predicts.
2. according to the organism ER affinity rapid screening Forecasting Methodology described in the claim 1 based on the receptors bind pattern, it is characterized in that according to QSAR discrimination model and the forecast model of the relation foundation that has affinity data contamination thing and receptors bind energy, hydrogen bond action pattern and arrival receptor acting site these receptors bind patterns of complexity and affinity index, and apply it in the acceptor affinity differentiation prediction of estrogen receptor affinity unknown compound based on receptor structure.
3. according to the organism ER affinity rapid screening Forecasting Methodology described in the claim 1 based on the receptors bind pattern, it is characterized in that the affinity index classification can determine that ratio is less than 10 by the ratio between compound and target recipient affinity and the acceptor native ligand affinity in the step (1)
-5The time think that compound is no affinity compound, 10
-5With 10
-2Between the time think that compound has weak affinity, greater than 10
-2The time compound have high affinity, this wherein can be divided into two classes again, 10
-2With 10
-1Between the time think that compound has the affinity of medium tenacity, greater than 10
-1The time think that compound has strong affinity; Correspond respectively to logRBA＜-3 ,-3≤logRBA＜0, logRBA 〉=0, wherein logRBA 〉=0 is divided into 0≤logRBA＜1 and logRBA 〉=1 liang class again.
4. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that testing under the estrogen receptor three-dimensional structure condition of unknown of using in the step (2), the receptor structure mould is built and can be adopted point mutation, homology mould construction method according to homology; When unknown ER and known ER homology were higher than 90%, ligand binding domain only had several residue differences, and its protein folding pattern is basic identical, adopted the method for point mutation to replace minority to the residue that folding pattern does not play a decisive role, and set up unknown structure ER model; For the unknown ER of homology difference, use target sequence from ncbi database, the method that adopts ESyPred3D, Spark2 homology mould to build makes up receptor model; The homology of mER α and hER α is the highest, only has a few residue to change in the LBD district, in the residue of composition active pocket a residue difference is only arranged, and can consider to adopt point mutation process to set up mER α receptor model; And the homology of lizard and rainbow trout ER and hER α is less than 90%, thereby can utilize the webservers such as ESyPred3D, Spark2 to make up both ER homology models, utilizes PROCHECK that the receptor model that makes up is carried out the rationality evaluation.
5. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that the compound structure and the energy-optimised use Tripos field of force in the step (3), electric charge is chosen as Gasteiger-H ü ckel electric charge, the energy convergence is 0.05kcal/mol, and maximum iteration time is set to 1000 times; Use FlexX molecular docking method that compound and estrogen receptor activity pocket are carried out molecular docking.
6. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that described in the step (3) in conjunction with free energy E
BindingCalculate acquisition by molecular docking method FlexX, butt joint failure E
BindingAssignment is 20.
7. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that the hydrogen bond action pattern described in the step (3) includes the identification in hydrogen bond action site between organic pollutants and hormone receptor and forms the definite of hydrogen bond number, N
HBThe hydrogen bond action number of expression compound and active pocket residue; Each indieating variable H represents whether Key residues, water of crystallization etc. form hydrogen bond in compound and the ER active pocket, and the indieating variable that forms the correspondence of hydrogen bond action is made as 1, otherwise is made as 0.
8. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that organic contaminant hydrophobicity parameter l ogP in the step (4) can adopt computing method such as fragment constant method or data base querying, document retrieval method to obtain, description characterizes its transmission and is transported to the complexity of target point and the relation of reconditioning and effective dose because of the structure difference causes its transmission transport features in cell, tissue etc.
9. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, it is characterized in that the described plant estrogen of step (5) is the more special ER part of a class, has special binding pattern with ER, when low concentration, show weak estrogen active, and after concentration raises, show the antiestrogenic ability, as seen itself and estrogen receptor have special binding pattern, then increase indieating variable X in screening
1Indicate and differentiation.
10. according to each described organism ER affinity rapid screening Forecasting Methodology in the claim 1～3 based on the receptors bind pattern, the discrimination model feature that it is characterized in that the strong and weak grade of organic contaminant described in the step (6) and hormone receptor affinity is: the hydrogen bond action pattern between analysis of compounds and active pocket amino acid residue, characterize the complexity that the organic contaminant transmission is transported to target point with logP, characterize the hydrogen bond that is subjected to body characteristics target point with indieating variable H and form situation, N is set
HBVariable is to hydrogen bond number counting, the binding energy E of computerized compound and estrogen receptor
Binding, butt joint failure E
BindingAssignment is 20, uses indieating variable X
1Expression has or not plant estrogen.Employing mahalanobis distance method is set up the discriminant function Y=a to pollutant-estrogen receptor affinity power is differentiated
1LogP+a
1E
Binding+ a
3N
HB+ a
4X
1+ a
5H ...
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