CN103093100B - The construction process of anthocyanin antioxidant activity three-dimensional quantitative structure-activity relationship model - Google Patents
The construction process of anthocyanin antioxidant activity three-dimensional quantitative structure-activity relationship model Download PDFInfo
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Abstract
The present invention relates to the construction process of anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model, described method is taking the anthocyanogen antioxidant of known activity as research object, utilize 3D-QSAR technology, setting up anthocyanogen antioxidant three-dimensional quantitative structure-activity relationship model, the technology such as field of force of molecule method and molecule likeness coefficient analytical method analysis, molecular conformation optimization, parameter optimization of employing sets up structure activity relationship model accurately. Constructed model can the activity value of the unknown active compound of fast prediction, and can rationally explain the relation of anthocyanin antioxidant activity size and its constitutional features.
Description
Technical field
The present invention relates to the construction process of a kind of anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model and application, it is specifically related to utilize the anthocyanogen material of known activity for research object, build the method for antioxidant activity three-dimensional quantitative structure-activity relationship, and the model utilizing structure carries out the prediction of unknown compound activity and the reasonable explaination of structure activity relationship.
Background technology
Free radical is a kind of intermediate product produced in organism vital movement. Body is under normal circumstances, the generation of free radical and elimination are in running balance, if but interior free yl produces too much or does not remove in time, body will be had destruction by too much free radical, cause the damage of human normal cell and tissue, thus cause a lot of disease, such as cardiovascular disorder, aging, tumour, senile dementia etc.
In view of the damage of excessive radical pair body, so the material that some must be had can to alleviate or eliminate free radical harm, playing oxidation-resistance, that this kind of material is exactly antioxidant.
Antioxidant from refer in a broad sense all can direct scavenging free radicals, or suppress to start free chain reaction, terminate free radical reaction, or the compound of endogenous anti-oxidative levels of substance can be improved. Antioxidant is generally divided into two classes by its source, and a class is synthetized oxidation preventive agent, and a class is natural antioxidants.
Synthetized oxidation preventive agent common at present has BHT (DBPC 2,6 ditertiary butyl p cresol), BHA (cloves hydroxyl phenylmethylether), TBHQ (Tert. Butyl Hydroquinone). The oxidation-resistance of synthetized oxidation preventive agent is very strong, but along with people understanding and research go deep into, human body can be damaged by these materials so that the interpolation of synthetized oxidation preventive agent in food is very restricted, so exploring natural antioxidants to become a research tendency.
That studies at present can mainly contain Polyphenols, vitamins, polysaccharide, terpene class, flavonoid, polypeptide class etc. as the material of natural antioxidants. These materials are all generally derive from plant, safety, nontoxic, are studied widely as functional food nutritional factor.
Three-dimensional quantitative structure-activity relationship model is a kind of physico-chemical property parameter by molecule or structural parameter, with mathematics and statistics means quantitative examination organic molecule and interaction of biomacromolecules, organic molecule in the method for the physiological correlations matter such as biological body absorption, distribution, metabolism, excretion. Now widely used 3D-QSAR research method mainly contains and compares molecule position analytical method (CoMFA) and molecule likeness coefficient analytical method (CoMSIA).
Along with the development of science and technology and continually developing of Theoretical Calculation simulation software, the research of structure activity relationship have also been obtained and develops significantly. 3D-QSAR mainly considers the 3 D stereo conformation of compound molecule, this is very crucial on the impact of activity on sign three-dimensional conformation, it can reflect the relation of the Stable conformation of molecule under specified conditions and biological activity more accurately, disclose the reactive site of molecule, and then the mechanism of explaination activity relationship. Therefore structure activity study is just playing more and more important effect in anti-oxidant activity.
Summary of the invention
The present invention is directed to the deficiency that antioxidant active mechanism is explained by prior art, it provides the construction process of a kind of anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model and application. Described method is taking the anthocyanogen antioxidant of known activity and structure as research object, utilize 3D-QSAR technology, adopt field of force of molecule method (CoMFA) and molecule likeness coefficient analytical method (CoMSIA) to analyze, set up anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model accurately by technology such as molecular conformation optimization, parameter optimizations. Constructed model can the activity of the unknown active compound of fast prediction, and can rationally explain the relation of anthocyanin antioxidant activity size and its constitutional features.
For achieving the above object, the present invention is adopted following scheme:
A construction process for anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model, comprises the following steps:
(1) measuring the anti-oxidant activity size of anthocyanogen material, and be test set and training set by its random packet, index of biological activity adopts the negative logarithm of anti-oxidant activity to represent;
(2) use software analysis to obtain the three-D space structure of the compound in training set and test set, obtain the three-D space structure model optimized through Optimum configuration;
(3) optimizing in step (2) based on the public rigid backbone of the three-D space structure model obtained, the molecule that anti-oxidant activity is maximum in training set is superimposed as template carries out molecule;
(4) field of force information searched around superimposed rear compound with Small-molecule probe calculates field of force value;
(5) the biological activity value of the compound in field of force information step (4) obtained and training set carries out partial least square method (PLS) recurrence, obtains anthocyanogen material antioxidant activity three-dimensional quantitative structure-activity relationship model.
Using software analysis to obtain the three-D space structure of compound in described step (2), described software refers to SYBYL-X1.2 software; Optimum configuration in described step (2) uses the Tripos field of force to be optimized, and adds Gasteiger-H �� ckel electric charge, and energy convergence is limited to 0.005kcal/mol, and maximum iteration time is 1000 times; The folding method adopted in described step (3) is AlignDatabase method; The Small-molecule probe adopted in described step (4) is sp3The carbon atom of hydridization; The field of force value calculated in described step (4) is CoMFA or CoMSIA field of force value; The biological activity value of the compound in field of force information and training set is carried out partial least square method (PLS) recurrence by described step (5), with cross validation coefficient q2It is greater than 0.5, non-crossing checking coefficient r2It is greater than the reasonableness that 0.8 is characterization model.
In a better embodiment, described construction process comprises following concrete steps:
(1) according to constructional feature and the active size of aldehydes matter, to 25 anthocyanogen material random packet, 18 compounds are chosen as training set, 7 remaining compositions test set (see table 1); Index of biological activity adopts oxyradical receptivity (OxygenRadicalAbsorptionCapacity, ORAC) ORAC, and a great deal of (��m oleTrolox/mole) being namely equivalent to Trolox calculates;
(2) molecule optimization: the three-D space structure building compound in training set and test set with SYBYLX-1.2 analysis software. Selecting the Powell method under Tripos position, charge type is Gasteiger-H �� ckel, and energy convergence is limited to 0.005kcal/mol, and maximum iteration time is 1000 times; Other parameters selection default values, carry out molecule optimization, find the Optimum configuration of each molecule;
(3) molecule is superimposed: the Optimum configuration obtaining each molecule after molecule optimization, chooses the highest active compound in training set and, as template molecule, taking phenyl ring as public skeleton, adopts AlignDatabase method to carry out molecule superimposed;
(4) field of force energy balane: utilize sp3The carbon atom of hydridization does Small-molecule probe group, calculates the interaction energy of probe moieties and each molecule on each space networks lattice point, namely obtains the field of force energy information around superimposed rear compound;
(5) model is set up: in the field of force obtained above Energy value and training set, the biological activity value of compound carries out partial least square method (PLS) recurrence, first adopt and take out a change method and carry out cross validation analysis (leave-one-out), obtain cross validation relation conefficient q2With best number of principal components n, then utilize the best number of principal components obtained to carry out non-crossing checking and analyze (No-Validation), obtain anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model, with cross validation coefficient q2It is greater than 0.5, non-crossing checking coefficient r2It is greater than the reasonableness that 0.8 is characterization model, q2The ability being worth more high expression activation analysis is more strong.
It is an advantage of the invention that:
1, adopting SYBYL software, the anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model by CoMFA and CoMSIA method establishment, the model of foundation has good predictive ability.
2, the three-dimensional quantitative structure-activity relationship model set up is utilized, it is possible to the well activity of prediction unknown compound, it is possible to rationally explaination anthocyanin antioxidant activity mechanism.
Embodiment
Below by embodiment, the present invention is specifically described, but technical solution of the present invention is not limited to following cited enforcement mode.
Embodiment 1:
Choose 25 kinds of anthocyanin compound (table 1) as research object, measure the ability of 25 kinds of material scavenging activated oxygen, with oxyradical receptivity (OxygenRadicalAbsorptionCapacity, ORAC) for index of biological activity; Choosing 18 kinds in the 25 kinds of compounds determining anti-oxidant activity at random as training set (table 1), 25 kinds of compounds, as test set, are divided into groups by 7 kinds; Under SYBYLX-1.2 software, draw the structure iron of these 25 kinds of anthocyanin compound; Selecting the Powell method under Tripos position, charge type is Gasteiger-H �� ckel, carries out molecule optimization, obtains the Optimum configuration of each molecule; Training set compound is chosen the highest active compound as template molecule (in table 1 compound 7), select phenyl ring to be public skeleton, adopt AlignDatabase method to carry out molecule superimposed; Calculate CoMFA field of force value, comprise three-dimensional field-effect and electrostatic field effect value, utilize sp3The carbon atom of hydridization as probe moieties, calculate on each space networks lattice point probe moieties respectively with the interaction energy of 18 molecules, this Energy value is the field of force energy information calculated; Adopt partial least square method (PLS) to be returned by the activity value of three-dimensional field-effect value and electrostatic field effect value and compound, obtain cross validation coefficient q2Value is 0.857, and best number of principal components is 4, non-crossing checking coefficient r2Value is 0.957, standard deviation s be 0.153, F inspection value is 73.267; Obtain anthocyanogen antioxidant activity of antioxidant 3D-QSAR CoMFA model. Namely consider the relation of anti-oxidant activity and anthocyanogen structure from three-dimensional field-effect and electrostatic field effect, utilize the field-effect potentiometric map reasonable dismissal antioxidant active mechanism obtained. By the prediction in test set 7 compound activity values, well demonstrate the accuracy of model and good predictive ability, see table 1.
Embodiment 2:
Choose 25 kinds of anthocyanin compound as research object (table 1), measure the ability of 25 kinds of material scavenging activated oxygen, with oxyradical receptivity (OxygenRadicalAbsorptionCapacity, ORAC) for index of biological activity; Choosing 18 kinds at random as training set in the 25 kinds of compounds determining anti-oxidant activity, 7 kinds as test set; Under SYBYLX-1.2 software, draw the three-D space structure of each compound; Selecting the Powell method under Tripos position, charge type is Gasteiger-H �� ckel, and other parameters, with embodiment 1, carry out molecule optimization, obtain the Optimum configuration of each molecule; Carrying out superimposed to the molecule Optimum configuration drawn, choosing active the highest compound work (in table 1 compound 7) in training set compound is template molecule, selects phenyl ring to be public skeleton, adopts AlignDatabase method to carry out molecule superimposed; Calculating molecule likeness coefficient CoMSIA field of force value, comprises three-dimensional field-effect and electrostatic field effect value, hydrophobic field-effect value, hydrogen bond receptor field and hydrogen bond donor field-effect value utilize sp3The carbon atom of hydridization as probe moieties, calculate on each space networks lattice point probe moieties respectively with the interaction energy of 18 molecules, this Energy value is the field of force energy information calculated; Adopt partial least square method (PLS) to 5 effect field values respectively activity value with compound return, obtain cross validation coefficient q2Value is 0.729, and best number of principal components is 4, non-crossing checking coefficient r2Value is 0.856, standard deviation s be 0.134, F inspection value is 19.247; Obtain anthocyanogen antioxidant activity of antioxidant 3D-QSAR CoMSIA model, namely from three-dimensional field-effect and electrostatic field effect, hydrophobic field-effect, the relation of anti-oxidant activity and anthocyanogen structure is considered in hydrogen bond receptor field and hydrogen bond donor field-effect, utilizes the relation of field-effect potentiometric map reasonable dismissal anti-oxidant activity and the anthocyanogen structure obtained. Predict finally by the carrying out of in test set 7 compound activity values, well demonstrate the accuracy of model and good predictive ability, see table 1.
The molecular structure of table 1 anthocyanogen and ORAC active testing value and predictor
Note standby:
a, test set compound
b, the template compound in training set
c, ORAC value calculates with Trolox a great deal of, represents with a ��m olTrolox/mol.
Other, Glc, glucoside (glucosyl group); Gal, galacoside (galactosyl); Ara, arabinoside(pectinose base); Rut, rutinoside (rutinose base); Sam, sambubioside (mulberry cloth disaccharide base); Sop, sophoroside (Chinese scholartree sugar base); Cou-sam, sambubiosideacylwithp-coumaricacid(are to coumaric acyl mulberry cloth disaccharide base); Cou-rut, rutinosideacylwithp-coumaricacid(are to coumaric acyl rutinose base); Cou-sop:sophorosideacylwithp-coumaricacid (to coumaric acyl Chinese scholartree sugar base); Mal-glc, glucosideacylwithmalonicacid (malonyl-glucosyl group).
Claims (7)
1. a construction process for anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model, comprises the following steps:
(1) anthocyanin compound in table 1 is chosen as research object, measure the ability of 25 kinds of described anthocyanin compound scavenging activated oxygen, taking oxyradical receptivity as index of biological activity, described index of biological activity adopts the negative logarithm of anti-oxidant activity to represent; Described anthocyanin compound is chosen 18 kinds at random as training set, remain 7 kinds as test set, 25 kinds of described anthocyanin compound are divided into groups;
(2) use software analysis to obtain the three-D space structure of the compound in training set and test set, obtain the three-D space structure model optimized through Optimum configuration;
(3) optimizing in step (2) based on the public rigid backbone of the three-D space structure model obtained, the molecule that anti-oxidant activity is maximum in training set is superimposed as template carries out molecule;
(4) field of force information searched around superimposed rear compound with Small-molecule probe calculates field of force value, described field of force value is CoMFA or CoMSIA field of force value, wherein said CoMSIA field of force value comprises three-dimensional field-effect and electrostatic field effect value, hydrophobic field-effect value, hydrogen bond receptor field and hydrogen bond donor field-effect value;
(5) the biological activity value of the compound in field of force information step (4) obtained and training set carries out partial least square method (PLS) recurrence, obtains anthocyanogen material antioxidant activity three-dimensional quantitative structure-activity relationship model.
2. construction process as claimed in claim 1, it is characterised in that, described step (2) use software analysis obtain the three-D space structure of compound, described software refers to SYBYL-X1.2 software.
3. construction process as claimed in claim 1, it is characterized in that, the Optimum configuration in described step (2) uses the Tripos field of force to be optimized, and adds Gasteiger-H �� ckel electric charge, energy convergence is limited to 0.005kcal/mol, and maximum iteration time is 1000 times.
4. construction process as claimed in claim 1, it is characterised in that, the folding method adopted in described step (3) is AlignDatabase method.
5. construction process as claimed in claim 1, it is characterised in that, the Small-molecule probe adopted in described step (4) is sp3The carbon atom of hydridization.
6. construction process as claimed in claim 1, it is characterised in that, the biological activity value of the compound in field of force information and training set is carried out partial least square method (PLS) recurrence by described step (5), with cross validation coefficient q2It is greater than 0.5, non-crossing checking coefficient r2It is greater than the reasonableness that 0.8 is characterization model.
7. the construction process as described in as arbitrary in claim 1-6, wherein said method comprises following concrete steps:
(1) according to constructional feature and the active size of aldehydes matter, 25 anthocyanogen material random packet in his-and-hers watches 1, choose 18 compounds as training set, 7 remaining composition test sets; Index of biological activity adopts oxyradical receptivity ORAC to calculate;
(2) molecule optimization: the three-D space structure building compound in training set and test set with SYBYLX-1.2 analysis software, select the Powell method under Tripos position, charge type is Gasteiger-H �� ckel, energy convergence is limited to 0.005kcal/mol, and maximum iteration time is 1000 times; Other parameters selection default values, carry out molecule optimization, find the Optimum configuration of each molecule;
(3) molecule is superimposed: the Optimum configuration obtaining each molecule after molecule optimization, chooses the highest active compound in training set and, as template molecule, taking phenyl ring as public skeleton, adopts AlignDatabase method to carry out molecule superimposed;
(4) field of force energy balane: utilize sp3The carbon atom of hydridization does Small-molecule probe group, calculates the interaction energy of probe moieties and each molecule on each space networks lattice point, namely obtains the field of force energy information around superimposed rear compound;
(5) model is set up: in the field of force obtained above Energy value and training set, the biological activity value of compound carries out partial least square method (PLS) recurrence, and first employing is taken out a change method and carried out cross validation analysis, obtains cross validation coefficient q2With best number of principal components n, then utilize the best number of principal components obtained to carry out non-crossing checking and analyze, obtain anthocyanogen antioxidant activity of antioxidant three-dimensional quantitative structure-activity relationship model, with cross validation coefficient q2It is greater than 0.5, non-crossing checking coefficient r2It is greater than the reasonableness that 0.8 is characterization model, q2The ability being worth more high expression activation analysis is more strong.
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| CN102262715A (en) * | 2011-06-01 | 2011-11-30 | 山东大学 | Method for constructing three-dimensional quantitative structure activity relationship model of B-cell lymphoma-2 (Bcl-2) protein inhibitor and application of method |
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| CN102262715A (en) * | 2011-06-01 | 2011-11-30 | 山东大学 | Method for constructing three-dimensional quantitative structure activity relationship model of B-cell lymphoma-2 (Bcl-2) protein inhibitor and application of method |
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