CN101736406A - Method for discovering active components of traditional Chinese medicine by metabolic forecast and virtual sieving - Google Patents
Method for discovering active components of traditional Chinese medicine by metabolic forecast and virtual sieving Download PDFInfo
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Abstract
The invention discloses a method for discovering the active components of a traditional Chinese medicine by metabolic forecast and virtual sieving. The method comprises the following steps: (1) collecting all the chemical components with already corroborated structures in the researched traditional Chinese medicine and forecasting a metabolic product which is probably generated in vivo by these chemical components; (2) constructing a library of molecules for the chemical components which are contained in the traditional Chinese medicine and have the already corroborated structures and the forecasted metabolic product thereof; (3) constructing a corresponding three-dimensional structure model with one or more acting target spots according to the functional indications or the pharmacological action of the traditional Chinese medicine; (4) carrying out virtual docking on the library of the molecules and the target spot model by software, grading the docking result of each molecule in the library of the molecules, comparing with reference molecules and sieving out the molecules the virtual activity of which is positive; and (5) carrying out biological activity experimental verification on the chemical components the virtual activity of which is positive, thus discovering the active components representing the functional indications or the pharmacological action of the traditional Chinese medicine. The invention can disclose the active components of the traditional Chinese medicine comprehensively.
Description
Technical field
The present invention relates to a kind of research method of active ingredient of Chinese herbs, particularly relate to a kind of method of finding active ingredient of Chinese herbs by metabolic forecast and virtual screening.
Background technology
The traditional Chinese medicine ingredients complexity, mechanism of action complexity.Understand fully all activeconstituentss of Chinese medicine and understand fully that the mechanism of action is two importances in modernization of cmm field.Understand fully all activeconstituentss, need finally to understand fully in the chemical ingredients that Chinese medicine or compound contained simply comprehensively, which composition cure mainly with the function of this Chinese medicine or pharmacological action relevant, have specific biological activity.In addition, the contained chemical ingredients of Chinese medicine might be through just producing activity after the metabolism after entering human body, and therefore, whether the various meta-bolitess of comprehensively understanding fully the contained chemical ingredients of this Chinese medicine cure mainly its function or pharmacological action is contributed also to some extent and is very important.Understand fully the mechanism of action, site of action that then must the contained chemical ingredients of at first clear and definite Chinese medicine has promptly produced effect to which target spot.
At present, domestic research method about active ingredient of Chinese herbs is a lot, has also obtained a lot of achievements, has illustrated the part chemical ingredients of some Chinese medicine and the activity of meta-bolites thereof to a certain extent.But also there are a lot of problems in existing method and technology: the first, often be absorbed in the research of one or more compositions or efficient part, and be difficult to disclose the activeconstituents of Chinese medicine comprehensively; The second, be difficult to disclose the effect of the various meta-bolitess of chemical composition of Chinese materia medica comprehensively; The 3rd, the research target spot is often comparatively single, is difficult to disclose the action rule of Chinese medicine multicomponent, many target spots; The 4th, research cycle is long, cost is big, efficient is low.
In recent years, the development gradually of area of computer aided drug research method and perfect is for the research active ingredient of Chinese herbs provides new means.
Summary of the invention
At the deficiencies in the prior art part, the object of the present invention is to provide a kind of method by metabolic forecast and virtual screening discovery active ingredient of Chinese herbs, this method can disclose the activeconstituents of Chinese medicine comprehensively.
For achieving the above object, the present invention adopts passes through metabolic forecast and virtual screening method finds that the method for active ingredient of Chinese herbs comprises the steps:
The chemical structure of the meta-bolites of the contained chemical ingredients of prediction Chinese medicine
Collect the contained chemical ingredients of proving conclusively chemical structure of this Chinese medicine, by software or predict the chemical structure of these chemical ingredientss meta-bolites in vivo according to the drug metabolism theory;
Set up library of molecules
Be built into library of molecules with resulting various prediction meta-bolitess in software the chemical ingredients of proving conclusively chemical structure that this Chinese medicine is contained and the above-mentioned steps;
Set up the three-dimensional model of action target spot
Function according to this Chinese medicine cures mainly or pharmacological action, select corresponding target spot to carry out modeling, for target spot to be studied, can directly utilize by the target spot 3 d structure model of experiment confirm, also can use software to set up its 3 d structure model by the homology modeling method;
Virtual screening
A. with software above-mentioned steps library of molecules of setting up and the target spot molecular model of being set up are carried out virtual butt joint, utilize score function that the butt joint result of each molecule in the library of molecules is marked, if have a plurality of scorings with a part, mean with a plurality of scorings is final scoring, the absolute value Si of the final scoring of gained is used for the result and judges that i is a natural number;
B. selecting has clear and definite active positive drug or compound as the reference molecule to research target spot, and it is carried out virtual the butt joint with this target spot molecular model, and obtains the butt joint scoring, and the absolute value R of this butt joint scoring is used for the result and judges.
C. the result judges: Si 〉=R * x%, result are virtual active positive, Si＜R * x%, the result is virtual active negative, described x% representative is got different value according to different target spots, different reference molecule, usually x%＞50% with respect to the ratio of reference molecular docking scoring;
The biological activity checking
The virtual active male molecule that above-mentioned steps is screened, with in the body or external pharmacological evaluation carry out biological activity checking, all molecules by the biological activity checking are the activeconstituents that produces after activeconstituents that this Chinese medicine contains or the contained chemical ingredients metabolism of this Chinese medicine.
Chinese medicine described in the such scheme comprises herbal mixture and single medicinal material.
This step of three-dimensional model of setting up action target spot in the such scheme can be positioned at before this step of chemical structure of the meta-bolites of predicting the contained chemical ingredients of Chinese medicine.
The present invention has following advantage:
(1) analyzes at the chemical ingredients of all known structure of waiting to study Chinese medicine, can disclose the activeconstituents to specific target spot of this Chinese medicine comparatively all sidedly;
(2) effect of their meta-bolitess is considered in the effect of the chemical ingredients of not only considering Chinese medicine and being contained itself simultaneously, is directly to produce drug effect or through producing drug effect after the metabolism thereby can illustrate chemical ingredients that this Chinese medicine contains;
(3) obtain the potential activeconstituents by virtual screening earlier, carry out biological activity test again, compare, avoided the blindness of screening with traditional research method;
(4) this method can be finished many target spots lateral reactivity evaluation of a large amount of chemical ingredientss at short notice, compares with traditional research method, and efficient is higher;
(5) most of implementation step of this method is finished by Computing, compares with traditional research method, and research cost is lower.
Description of drawings
Fig. 1 is the meta-bolites molecule of the contained chemical ingredients of Chinese medicine White Mulberry Root-bark that obtains of software prediction.
Fig. 2 is the library of molecules that contained chemical ingredients of Chinese medicine White Mulberry Root-bark and prediction meta-bolites thereof are formed.
The part that Fig. 1, Fig. 2 have only drawn full figure.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) chemical structure of the meta-bolites of the contained chemical ingredients of prediction White Mulberry Root-bark
By retrieving relevant chemline and in conjunction with literature survey, obtain the contained chemical ingredients molecule of proving conclusively structure of Chinese medicine White Mulberry Root-bark and amount to 238, utilization software PALLAS predicts the chemical structure of the possible meta-bolites of White Mulberry Root-bark chemical ingredients, obtain predicting the meta-bolites molecule, see Fig. 1, amount to 3293;
(2) set up White Mulberry Root-bark chemical ingredients and prediction meta-bolites library of molecules thereof
With the chemical structure that Chemsketch software is drawn contained chemical ingredients of White Mulberry Root-bark and their prediction meta-bolites molecule, carry out conformation optimization with CORINA software, set up White Mulberry Root-bark chemical ingredients and prediction meta-bolites library of molecules thereof, see Fig. 2;
(3) set up the target spot molecule 3 d structure model of Chinese medicine White Mulberry Root-bark diuretic properties
According to the effect of White Mulberry Root-bark " inducing diuresis to remove edema ", select the important target spot mineralcorticoid receptor of diuretic properties to carry out modeling.The three-dimensional structure of mineralcorticoid receptor is numbered 2AA2 from Protein Data Bank, removes with text editor and anhydrates and part, is optimized with Molegro Virtual Docker software;
(4) activeconstituents to Chinese medicine White Mulberry Root-bark chemical ingredients and meta-bolites thereof carries out virtual screening
Dock computing in Molegro Virtual Docker software, the butt joint that is provided each molecule by score function MolDockScore is marked, and concrete steps are:
A. start Molegro Virtual Docker software, import the 3 d structure model of the plain acceptor of having optimized of target spot mineralocorticoid;
B. detect the active region of target spot: the active region that this experiment detects target spot altogether has 5, choose wherein with an active region that carries part AS4_201 binding as docking the site;
C. import White Mulberry Root-bark chemical ingredients and meta-bolites library of molecules, select target spot to carry part AS4_201 as the reference molecule;
D., the various operating parameters of Molegro Virtual Docker software to connection module are set;
E. move connection module is carried out virtual butt joint computing;
F. operation result is analyzed, adopted the built-in BP artificial neural network of software to set up mathematical model, analyze the mutual relationship of various parameters and, and provide the MolDockScore scoring of the various orientations (pose) of each ligand molecular butt joint result's contribution;
G. according to MolDockScore scoring all pose are sorted, and compare with the scoring of reference molecule.The MolDockScore scoring of reference molecule AS4_201 is for-153.904.With AS4_201 is that reference is judged the butt joint result: R=153.904, set x%=85%, in White Mulberry Root-bark chemical ingredients and the meta-bolites library of molecules, totally 20 of the chemical ingredientss of Si 〉=R * x%=153.904 * 85%=130.818, see Table 1, these compositions have virtual activity (theoretical active).
Table 1 is at the result of mineralcorticoid receptor (2AA2) virtual screening
| Sequence number | Chemical ingredients | Scoring | Sequence number | Chemical ingredients | Scoring |
| ??1 | Mulberry furans (mulberrofuran) D | ??-156.254 | ??11 | Mulberry furans D 05 | ??-135.445 |
| ??2 | Mulberry furans D 01 | ??-155.536 | ??12 | Sanggenon (sanggenone) K 10 | ??-135.099 |
| ??3 | Mulberry furans D 04 | ??-147.429 | ??13 | Mulberry furans |
??-134.179 |
| ??4 | Mulberry furans D 02 | ??-144.956 | ??14 | Mulberry furans B | ??-134.135 |
| ??5 | Mulberry furans element (albafuran) A 03 | ??-138.766 | ??15 | Sanggenon K 06 | ??-133.932 |
| Sequence number | Chemical ingredients | Scoring | Sequence number | Chemical ingredients | Scoring |
| ??6 | The plain A 01 of mulberry furans | ??-138.24 | ??16 | Sanggenon |
??-133.498 |
| ??7 | Mulberry |
??-137.109 | ??17 | The plain A 05 of mulberry furans | ??-132.423 |
| ??8 | The plain A of mulberry furans | ??-136.687 | ??18 | Mulberrofuran A | ??-131.945 |
| ??9 | The |
??-136.589 | ??19 | Mulberry furans |
??-131.125 |
| ??10 | Mulberrofuran |
??-136.512 | ??20 | Mulberrofuran |
??-130.846 |
Annotate: 1. the numeral in the chemical ingredients title is meant the numbering of some structures of a plurality of prediction meta-bolitess of this chemical ingredients in the table.For example, be numbered 03 molecular structure in the prediction meta-bolites of mulberry furans D 03 expression mulberry furans D.2. interact because the energy that a prerequisite of successful butt joint is a system is lower and keep stable, thereby docking operation can be considered exergonic process, so the MolDockScore scoring is negative value, the absolute value of MolDockScore scoring is big more, shows that then the prediction activity is strong more.
(4) activity of the positive chemical ingredients mulberry furans D of the virtual activity of White Mulberry Root-bark diuretic properties checking
A.. materials and methods
A. material
SD rat (Sichuan Academy of Medical Sciences institute of lab animals provides), body weight 200～235g; Rat metabolic cage (joining the fecaluria separatory funnel).Mulberry furans D (biotechnology institute of Xihua Univ pharmaceutical chemistry research department provides) adds the normal saline solution that a small amount of tween 80 is made into 1mg/ml.
B. method
The screening of animal
Rat is put in the metabolic cage, and fasting 24h irritates stomach with physiological saline 25ml/kg.Collect urine in the 2h, the urine amount is qualified rat for irritating stomach amount 40% above person.
The diuresis experiment
Get 20 of the qualified male rats of screening, be divided into two groups at random, after water 24h is can't help in fasting, all irritate stomach and give the water load with physiological saline 25ml/kg.Before the administration, the light earlier rat lower abdomen of pressing drains surplus urine, subsequently administration.Administration group abdominal injection mulberry furans D, dosage 10mg/kg; The control group intraperitoneal injection of saline, dosage 10ml/kg.Collect urine, the total volume of urine that each mouse is discharged in the record 6h.
B. result
Physiological saline control group total volume of urine is 4.36 ± 0.87ml; Administration group total volume of urine is 5.68 ± 0.72ml, with control group utmost point significant difference (P＜0.01) is arranged, and shows that mulberry furans D has diuretic properties.
Embodiment 2
(1) of present embodiment, (2) step are with embodiment 1, (3) step then is to set up the target spot molecular model (1HVR) of screening hiv inhibitor according to the pharmacological action of the anti-HIV of White Mulberry Root-bark, (4) scoring of reference molecule XK2263 is-239.872 in the step, R=239.872, set x%=80%, in White Mulberry Root-bark chemical ingredients and the prediction meta-bolites library of molecules thereof, totally 15 of the chemical ingredientss of Si 〉=R * x%=239.872 * 80%=191.898 see Table 2.The virtual activity of these compositions is positive, has potential HIV and suppresses active.Experiment in vitro finds that mulberry furans O is to H9/HIV-1
IIIBIn the cell virus duplicated restraining effect, show the activity that it has anti-HIV.
Table 2 is at the result of anti-HIV target spot 1HVR virtual screening
| Sequence number | Chemical ingredients | Scoring | Sequence number | Chemical ingredients | Scoring |
| ??1 | |
??-221.933 | ??9 | The |
??-197.448 |
| ??2 | |
??-217.283 | ??10 | Mulberry furans M | ??-194.694 |
| ??3 | |
??-208.961 | ??11 | Phellinus ketone (kuwanon) |
??-194.576 |
| ??4 | Mulberry furans O | ??-202.319 | ??12 | |
??-193.988 |
| ??5 | |
??-201.471 | ??13 | Mulberry furans O 10 | ??-193.896 |
| ??6 | |
??-201.057 | ??14 | Mulberry furans O 05 | ??-193.833 |
| ??7 | |
??-199.017 | ??15 | Mulberry furans O 12 | ??-193.002 |
| ??8 | |
??-198.026 |
Claims (2)
1. find to it is characterized in that the method for active ingredient of Chinese herbs may further comprise the steps by metabolic forecast and virtual screening for one kind:
The chemical structure of the meta-bolites of the contained chemical ingredients of prediction Chinese medicine
Collect the contained chemical ingredients of proving conclusively chemical structure of this Chinese medicine, by software or predict the chemical structure of these chemical ingredientss meta-bolites in vivo according to the drug metabolism theory;
Set up library of molecules
Be built into library of molecules with resulting various prediction meta-bolitess in software the chemical ingredients of proving conclusively chemical structure that this Chinese medicine is contained and the above-mentioned steps;
Set up the three-dimensional model of action target spot
Function according to this Chinese medicine cures mainly or pharmacological action, select corresponding target spot to carry out modeling, for target spot to be studied, can directly utilize by the target spot 3 d structure model of experiment confirm, also can use software to set up its 3 d structure model by the homology modeling method;
Virtual screening
A. with software above-mentioned steps library of molecules of setting up and the target spot molecular model of being set up are carried out virtual butt joint, utilize score function that the butt joint result of each molecule in the library of molecules is marked, if have a plurality of scorings with a part, mean with a plurality of scorings is final scoring, the absolute value Si of the final scoring of gained is used for the result and judges that i is a natural number;
B. selecting has clear and definite active positive drug or compound as the reference molecule to research target spot, and it is carried out virtual the butt joint with this target spot molecular model, and obtains the butt joint scoring, and the absolute value R of this butt joint scoring is used for the result and judges;
C. the result judges: Si 〉=R * x%, result are virtual active positive, Si＜R * x%, the result is virtual active negative, described x% representative is got different value according to different target spots, different reference molecule, usually x%＞50% with respect to the ratio of reference molecular docking scoring;
The biological activity checking
The virtual active male molecule that above-mentioned steps is screened, with in the body or external pharmacological evaluation carry out biological activity checking, all molecules by the biological activity checking are the activeconstituents that produces after activeconstituents that this Chinese medicine contains or the contained chemical ingredients metabolism of this Chinese medicine.
2. a kind of method by metabolic forecast and virtual screening discovery active ingredient of Chinese herbs according to claim 1, it is characterized in that: described Chinese medicine comprises herbal mixture and single medicinal material.
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| CN106885665A (en) * | 2017-04-11 | 2017-06-23 | 西华大学 | A kind of Leaf Spring Suspension System multi-function test stand |
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Application publication date: 20100616 |