CN106407740A - Method for screening anti-androgen activity of flavonoid compounds based on molecular dynamics simulation - Google Patents
Method for screening anti-androgen activity of flavonoid compounds based on molecular dynamics simulation Download PDFInfo
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- 238000000329 molecular dynamics simulation Methods 0.000 title claims abstract description 30
- 238000012216 screening Methods 0.000 title claims abstract description 20
- 229930003935 flavonoid Natural products 0.000 title claims abstract description 14
- 235000017173 flavonoids Nutrition 0.000 title claims abstract description 14
- 230000002280 anti-androgenic effect Effects 0.000 title abstract description 3
- 239000000051 antiandrogen Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
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- 102000005962 receptors Human genes 0.000 claims description 40
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- 238000004088 simulation Methods 0.000 claims description 29
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
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- 238000004422 calculation algorithm Methods 0.000 claims description 3
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- 238000010792 warming Methods 0.000 claims description 3
- 244000180577 Sambucus australis Species 0.000 claims description 2
- 235000018734 Sambucus australis Nutrition 0.000 claims description 2
- 239000003098 androgen Substances 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
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- 238000012360 testing method Methods 0.000 abstract description 2
- 210000001503 joint Anatomy 0.000 abstract 1
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- ZAIANDVQAMEDFL-UHFFFAOYSA-N 3-methoxy-2-phenylchromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C(OC)=C1C1=CC=CC=C1 ZAIANDVQAMEDFL-UHFFFAOYSA-N 0.000 description 1
- YURQMHCZHLMHIB-UHFFFAOYSA-N 6-methoxy-2-phenyl-2,3-dihydrochromen-4-one Chemical compound C1C(=O)C2=CC(OC)=CC=C2OC1C1=CC=CC=C1 YURQMHCZHLMHIB-UHFFFAOYSA-N 0.000 description 1
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- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
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- YEHDMSUNJUONMW-UHFFFAOYSA-N methoxyflavone Natural products COC1=CC=CC=C1C1=CC(=O)C2=CC=CC=C2O1 YEHDMSUNJUONMW-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
The invention discloses a method for screening anti-androgen activity of flavonoid compounds based on molecular dynamics simulation. The method comprises the following steps: performing butt joint on an optimized tested flavonoid compound structure and a receptor file acquired by homology modeling, then performing molecular dynamics simulation for 20 nanoseconds by using a GROMACS software package, calculating a mean square root deviation of No.12 helix 8-20ns of a flavonoid compound receptor, importing data into a R language package, establishing a distinguishing model for the calculated standard deviation and residues, and removing inactive compounds from the compounds in a fuzzy area by inspecting the movement trajectories of the compounds in the receptor and the calculated mean square root deviation. According to the method disclosed by the invention, quantitative judgment is imported for the first time, the pre-judgment accuracy is improved by the combination of quantitativeness and qualitativeness, the distinction rate of inactive flavonoid and active flavonoid reaches 87.5%, the screening rate of the inactive flavonoid reaches 90%, the laboratory workload can be greatly reduced, the consumption of test products is reduced, resources are saved, and the prediction accuracy of QSAR can also be greatly improved, so QSAR can be really applied.
Description
Technical field
The invention belongs to biological field, particularly to one kind, flavonoid is investigated by molecular dynamics simulation
The change of configuration of thing and androgen receptor and the method for sieving the anti-male activity of flavone compound.
Background technology
Incretion interferent refers to simulate human hormone and upsets the material of human endocrine EVAC, not only affects
The reproductive system of biology, induction cancer, or even can bring disaster upon and the second filial generation, the third generation.Estrogen receptor, androgen receptor and thyroid
Receptor, as the important component part of nuclear receptor superfamily, is the important target spot of mediating endocrine interference effect.Divide in a part
Secrete chaff interference and can simulate natural hormone and activate these target spots, this effect is referred to as plan-female/hero/thyroxin effect, another portion
Divide incretion interferent can suppress the effect of natural hormone, this effect is referred to as anti-female/hero/thyroxin effect.At present
The endocrine disruption species of the correlation being reported are various, such as bisphenol-A class, phthalate, polychlorinated biphenyl, PBBs
Ethers etc..Moreover, the chemicals increasing newly every year are even more countless, need the potential endocrine to magnanimity chemicals to do
Disturb activity and carry out high efficiency screening.For the incretion interferent of this three receptoroid mediation, have been set up many experimental techniques
In order to screen.Screening technique main at present has based on internal biological marker method, group method, and the yeast in vitro tests is double
Hybridization, Reporter Gene Experiments method and competion experiment etc..But these experimental techniques are wasted time and energy, if fully relied on
They are come to carry out the examination of incretion interferent be unpractical.
Based on so some challenges, computer virtual screening incretion interferent becomes strong instrument and nondominant hand
Section, such as D-M (Determiner-Measure) construction effect relation (quantitative structure-activity relationship, QSAR) are
Through being widely used, and achieve a lot of achievements.The basis of QSAR method is structure by comparative compound thus predicting
Its activity, but in reality, have substantial amounts of compound structure similar, but there is the difference that activity has or not.That is, it is current
The similar principle of the structure-based shares activity of QSAR method only can predict active known to those the and similar chemical combination of structure
The activity of thing, is unable to judge that compound activity has or not.Therefore, during concrete practice, most researchers are only
Select active compound as object of study, often ignore the presence of those inactive compounds, this is that QSAR method is maximum
Defect, be also the true cause that QSAR effectively cannot be applied in predictive compound endocrine disrupting activity field.In order to
Make up this defect it is necessary to find the rapid and effective method that a kind of energy anticipation compound activity has or not.
Numerous studies show, compound produces endocrine disrupting mainly by following step：First, compound
To be combined with each other with receptor (occurring in ligand binding domain) and interact, reach a steady statue；Secondly, ligand-receptor
Complex carries out homology or Heterodimerization or tetramerization；Finally, dimer or the tetramer identify specific chromosomal DNA sequence
Row, and regulatory factor (including co-activation and the co-suppression factor) combines together, thus producing the regulation and control to target gene, that is, produces
Endocrine disrupting.Part is combined generation in ligand binding domain with androgen receptor according to the present invention, and this region has 11
Individual α spiral composition (for the unification nominally with other nuclear receptors, is directly named as H3, Article 3 spiral Article 2 spiral
Directly it is named as H4, the like).Research finds, the change of configuration in this region will directly affect the biological function of nuclear receptor, its
In the significantly position of H12 change.It is generally believed that part (namely micromolecular compound) enters the part knot of receptor
There is model ylid bloom action, electric interactions, hydrogen bond action, hydrophobic interaction etc., in these power in the residue closing in domain, with binding pocket
Collective effect under, part and receptor move, finally stable after ad-hoc location, Transcription could occur.For being subject to
For body, the change being mainly characterized by its H12 of motion, finally stablize in specific position, with other metastable spirals
One surface that activity factor/co-suppression factor combines together is provided.For part, the principal character of its motion is whether
Can be always present in calmodulin binding domain CaM, and whether can be in calmodulin binding domain CaM stable existence.Further, since androgen receptor belongs to core being subject to
In body family " oestrogen-like hormone receptor ", with differences such as Thyroid Hormone Receptors (Thyroid hormone receptor, TR), it is somebody's turn to do
Only there is homodimerization in receptor, will not be affected by other nuclear receptor transcription.Therefore, we can be examined by simulation meanses
Examine part, the motion of H12 carrys out anticipation in real living things system, the receptor active of corresponding small molecule.
Molecular dynamics simulation (molecular dynamics simulation, MD) is a kind of based on computer investigation
Atom and the analogue technique of molecular physicses motion.Its ultimate principle is, the initial state of given simulated system, relies on Newtonian mechanics
The motion of model molecule system, with sample drawn in the assemblage being made up of the different conditions of molecular system, thus counting system
Function formdifinite, and based on the result of function formdifinite further counting system macroscopic property.The method is a large amount of
For explaining the mechanism of drug activation target spot, but as a kind of accurate screening media, but always it is not employed.This technology
Can be used as the premise technology of QSAR predictive compound endocrine disrupting.
Molecular dynamicses technology once was used for identifying that having exciting and antagonism the Organic substance of ER (opened love by Zhang Aiqian etc.
Madder, Lin Yuan, Peng Sufen, Liu Lei, Gao Changan, Han Shuo go against. the identification side of a kind of organic estrogen receptor agonism and antagonism
Method [P]. Jiangsu：CN101381894,2009-03-11), but the method, only for ER, and is not introduced into the concept of albumen allosteric.
Yu Hongxia etc. once by molecular dynamicses technology be used for screening nuclear receptor mediating endocrine chaff interference (Yu Hongxia, Shi Wei,
King is little to enjoy. the virtual screening method [P] of the nuclear receptor mediating endocrine interfering material based on molecular dynamics simulation. Jiangsu：
CN201310288617.3,213-9-25), but the method is only capable of substantially being judged it is impossible to carry out quantitation by comparing waveform
Prediction, precision of prediction is low, poor practicability.
Content of the invention
The purpose of the present invention is according to the interaction relationship between androgen receptor and flavone compound, provides one kind
Based on computer technology, time saving and energy saving economic screening flavone compound anti-hero activity methods, it is chemical producting safety and risk
Assessment provides technical support.
To achieve these goals, the present invention employs the following technical solutions：A kind of yellow based on molecular dynamics simulation screening
Ketone compounds anti-hero activity methods, comprise the following steps：
(1) build the ligand-receptor complex molecular structure of flavone compound and androgen receptor；
(2) dynamics simulation is carried out to molecule ligand-receptor complex molecular structure；
(3) set up analog result and distinguish model；
(4) analog result is judged according to model：If compound is located at active region, judge that compound is anti-for having
Male activity；If compound is located at non-viable regions, judge compound for the male activity of nonreactive；If compound is located at confusion region
Domain, then carry out step 5 and six；
(5) in analog result, part, when A ring has methoxyl group and receptor is less than setting value in the hydrogen bond quantity that part is formed, judges
Judge compound for the male activity of nonreactive；
(6) receptor and part movement locus are observed, if the movement locus of part have had been detached from the combined mouth of androgen receptor
Bag, judges the male activity of compound nonreactive；If receptor " mousetrap " phenomenon after simulation process terminates, judge chemical combination
Thing has anti-male activity；
(7) as compound is all judged as the male activity of nonreactive through step 5 and six, then judge that compound, for the male activity of nonreactive, is otherwise sentenced
Seco compound is to have anti-male activity；
(8) CoMSIA forecast model is set up to the compound judging to have anti-male activity, prediction has anti-male activity chromocor compound
Active size.
In described step 1, the structure of ligand-receptor complex molecular structure adopts following steps：Build flavone compound
Molecular structure and androgen receptor initial state structure, carry out energy-optimised, and give Gasteiger-Huckel electric charge；Using
Part is respectively 0.5 and 0, chooses and dock to accessing receptor file, range threshold and the coefficient of expansion by the software of Sybyl7.3
Divide highest conformation as initial configurations, it is merged with receptor, form complex；
The initial state structure of described androgen receptor adopts the aminoacid sequence file of androgen receptor, imports Swiss-Model
In the webserver, then Blast search is carried out for template with the albumin crystal structure of ER α initial state.
Carry out dynamics simulation in described step 2, carried out using GROMACS software, part and receptor are all given
The force field parameter in the CHARMM27 field of force, wherein receptor carries for software, and the force field parameter of part is given by Swiss-Param；
Whole system is put in the model cube body box being occupied by TIP3P hydrone, complex is apart from the short distance on box border
Ensure the charge balance of system from for 1 nanometer, adding sodium ion or chloride ion；Realized whole with steepest descent method and conjugate gradient method
The energy convergence of individual system, then system is warming up to 300K and maintains always, and gives 1 normal atmosphere；Constraint receptor egg
Carry out the molecular dynamics simulation of 50ps, finally revocation constraint is simulated after white.
In described dynamics simulation, electric interactions use particle mesh Ewald algorithm, and Van der Waals force is with 1 nanometer
Truncation radius, step-length 2fs of simulation, a system carries out the simulation of 20ns.
Described analog result is distinguished model foundation and is adopted following steps：Choose 48 kinds of typical flavonoids as screening collection,
Build 48 flavone-androgen receptor compounds, system carries out molecular dynamics simulation using Gromacs after pretreatment,
System maintains 1atm, and truncation radius are set toDynamics simulation step-length is 2fs, and every 2ps preserves a conformation, each system
Carry out the dynamics simulation of 20ns；Then root-mean-square-deviation analysis is carried out to H12, the H12 of compound having anti-male activity is in 8ns
Keep stable, and the H12 of other systems is always maintained at fluctuating；H12 is imported R language in the root-mean-square-deviation of 8～20ns, obtains
Distinguish model.
The ultimate principle of the present invention is to combine using Molecular Dynamics Calculation androgen receptor to occur after test-compound
Change of configuration, forms hydrogen bond feelings based on H12 chain in 8～20ns time fluctuation situation, compound and receptor within 8～20ns time
Condition, part small molecule movement locus, part small molecule situation of fluctuation during simulating come whether synthetic determination test-compound has
Related receptor active.
The dynamic mistake that flavone compound combines rear interaction in androgen receptor can be simulated using the inventive method
Based on molecular dynamics simulation, journey, differentiates whether material has receptor resistance, then predicting these using CoMSIA model has
Resistance but activity unknown flavone compound activity.The method is with low cost, easy and simple to handle, for extensive prediction flavonoid
Compound anti-hero activity provides instrument firmly, and the flavonoid medicine also having anti-male activity for screening further provides and supports.
This method is firstly introduced rational judgment, and to improve the degree of accuracy of anticipation so that resisting with qualitatively and quantitatively combining
The differentiation rate of property and non-resistant flavone reaches 87.5%, and the rate that screens out of non-resistant flavone reaches 90%, can not only significantly cut down
Laboratory work amount, reduces trial target consumption, economizes on resources moreover it is possible to the accuracy of QSAR prediction be greatly improved so that QSAR energy
Enough real realization applications.
Brief description
Fig. 1 is the differentiation model of embodiment, and circle represents surveys active compound, and triangle represents actual measurement inactiveization
Compound.
Specific embodiment
Further illustrate the present invention by the following examples, but protection scope of the present invention is not limited only to embodiment.
(1) build the molecular structure of test-compound in chemdraw, in Gauss 09 software, use DFT method
B3lyp/6-311G* is basis set to carry out energy-optimised, then utilizes Sybyl7.3 software to give Gasteiger-Huckel electric charge.This
It is desirable that the free state structure of receptor in research, obtain the free state structure of ER from Protein Data Bank (PDB), its PDB compiles
Number it is 1A52, then using 1A52 as template, build the initiating structure of AR using the Swiss-Model webserver.Build
Result ramachandran map Ramachandran method is tested it was demonstrated that the reasonability of result.All structures are all checked with spdv, and the residue of disappearance is soft with this
The automatic polishing of part.Then the Surflex-dock module utilizing Sybyl7.3 software finds receptor Large molecule active mouth, will be tested
Compound opposed inlet bag respectively.Choose docking marking value highest compound conformation as activity conformation, it is closed with receptor
And, composition complex is used for molecular dynamics simulation.
(2) and then to the ligand-receptor complex building carry out molecular dynamics simulation.Molecular dynamics simulation all
It is based on GROMACS software kit, this software has faster computing speed compared to other molecular dynamicses softwares such as AMBER
Degree, is suitable for screening on a large scale.Part and receptor are all given with the CHARMM27 field of force, the wherein force field parameter of receptor is software
Carry, and the force field parameter of part has Swiss-Param to give.Whole system is put into the model being occupied by TIP3P hydrone
In cuboid box, the beeline apart from box border for the complex is 1 nanometer.In order to ensure the charge balance of system, in body
Sodium ion or chloride ion is added in system.Realize the energy convergence of whole system with steepest descent method and conjugate gradient method, be then
System is warming up to 300K and maintains always, and gives 1 normal atmosphere.Carry out the molecular dynamicses of 50ps after constraint receptor protein
Simulation, finally revocation constraint is simulated.Electric interactions use particle mesh Ewald (PME) algorithm, Van der Waals force
With 1 nanometer of truncation radius, step-length 2fs of simulation, a system typically carries out the simulation of 20ns.
(3) result according to simulation extracts the root-mean-square-deviation (root of receptor H12 (receptor-H12) locus
Mean square deviation, RMSD), calculate its standard deviation and residual using R language pack：RMSD (i)=a ×
Time (i)+b+ ε (i), wherein ε are residual errors, a and b is constant.Dependency between Criterion deviation and residual error, obtains and distinguishes
Model.When compound is located at active region it is believed that this compound is to have anti-male activity；But compound is located at non-viable regions
When it is believed that the male activity of this compound nonreactive；When compound is located at fuzzy region, then need to be determined whether.
(4) hydrogen bond (hydrogen bond) being formed in receptor-ligand interaction process is extracted according to analog result,
The hydrogen bond quantity that between analysis 8-20ns, receptor is formed in part.When part has methoxyl group in A ring and forms hydrogen bond between 8-20ns
Quantity is seldom it is believed that this compound nonreactive is male active.
(5) receptor and part movement locus are observed, if the movement locus of part have had been detached from the knot of androgen receptor
Heal up bag, judges the male activity of compound nonreactive；If receptor " mousetrap " phenomenon after simulation process terminates, judge
Compound has anti-male activity.
(6) using technical scheme (4)-(5), the compound of inactive combinational fuzzy group in technical scheme (3) is verified
And differentiation：If compound meets with regard to judging there is (no) activity in technical scheme (4) and (5) in this two groups, compound has
(no) activity.
(7) use CoMSIA module in sybyl software, based on the anti-male activity of known chromocor compound, set up CoMSIA pre-
Survey model, prediction is unknown active but judges the active size with anti-male activity chromocor compound.
Embodiment
Initial state receptor file builds：
AR belongs to " estrogenses " nuclear receptor, and its initial state structure does not obtain, but the albumin crystal structure of ER α initial state is
Pass through experiment by forefathers and obtain (PDB code:1A52).The feature of " estrogenses " nuclear receptor is in activated state/aepression
Substantially, therefore AR also has identical characteristics to H12 position difference.From American National Bioinformatics Institute data base (national
Center for biotechnology information, NCBI) obtain the aminoacid sequence file of AR, import Swiss-
In the Model webserver, then Blast search is carried out for template with 1A52.Will be in Pymol software after the completion of Blast search
Carry out lamination process, will newly build H11-H12 and be overlapped to experiment PDB file for overlapping referential with H11, the H12 building is closed
And the H1-H11 to original obtains new structured file, namely the initial state structure of receptor.During, the PDB of the AR of needs
File is 1T7T.
Ligand-receptor complex builds：
Using the present invention, pretreatment is carried out to albumen file and small molecule file, for further molecular docking and molecule power
Learn simulation.Draw the two-dimensional structure formula of small molecule in chemdraw12.0, then carried out with the MM2 module of chem3D12.0 just
Step optimizes.Optimize the structure obtaining and carry out quantum optimization with Gauss software.Wherein quantum optimization is carried out using DFT method,
Carry out on 6-311G* is basis set.Finally uniformly give Gasteiger-Huckel electric charge to all small molecules.All for point
The receptor file of subdynamics simulation also will carry out pretreatment.First with spdbv, the side chain of aminoacid defect is repaired,
In Sybyl7.3, atom is hydrogenated with to each albumen file, gives Gasteiger-Huckel electric charge simultaneously.
Using Sybyl7.3 Surflex-Dock module by small molecule to access receptor file.Searched with automatic search method
Seek docking pocket, range threshold and the coefficient of expansion are set to 0.5 and 0.Then by small molecule to access docking port bag, each
Small molecule is a conformation by obtain highest scoring, and the conformation that we choose highest scoring is initial as molecular dynamics simulation
Conformation.
The antiandrogen active setting up flavonoid distinguishes model：
Choose 48 kinds of typical flavonoids as screening collection, 48 flavone-AR complex are built using the present invention, system is through pre-
Carry out molecular dynamics simulation using Gromacs after process.Including the optimization of structure 10000 step steepest descent method, 50ps liter
Temperature balances and final simulation process to normal temperature and pressure (NPT) assemblage of 300K, 200ps.In simulation process, system maintains
1atm, truncation radius are set toDynamics simulation step-length is 2fs, and every 2ps preserves a conformation and is used for interpretation of result.
Each system carries out the dynamics simulation of 20ns, is then found by the analysis of the RMSD to H12, has anti-male activity
The H12 of compound be maintained for stable before 8ns, and the H12 of other systems is always maintained at fluctuating.We are by H12 in 8-
The RMSD of 20ns imports R language, obtains and distinguishes model, and 13 chromocor compounds are located at active area, 27 be located at inactive area,
7 are located at confusion region.The hydrogen bond quantity generating in analysis chromocor compound 8-20ns simulated time, when a certain compound is in A ring
It is believed that this compound is inactive in the case of having methoxyl group but seldom generating hydrogen bond.Prunusetin. in active region
(prunetin) due to having methoxyl group in A ring and little hydrogen bond is it is believed that the male activity of this compound nonreactive；7- in fuzzy region
Methoxy flavone is similarly the male activity of nonreactive.Additionally, in activearm, 6- methoxy flavanone shows " mousetrap "
Phenomenon, determines activity again；In nonactive group, 3- hydroxyl -6-methoxy-2-phenyl-4H-chromen-4-one directly in simulation process from combined mouth
Escape in bag, determine inactive again.By the present invention, 42 in 48 chromocor compounds can be made whether there is anti-hero
Activity；Clearly can be identified out, detectability is up to 90% for 27 in 31 nonreactive male activity chromocor compounds.Differentiate knot
Fruit passes through MDA-kb2 experimental result with us and result by references is consistent.
The above, be only presently preferred embodiments of the present invention, and not the present invention is done with any type of restriction.Every
Any simple modification, equivalent variations and the modification substantially above example made according to technology and the method for the present invention, all still
Belong in the range of technology and the method scheme of the present invention.
Claims (6)
1. a kind of molecular dynamics simulation screening flavone compound anti-hero activity methods that are based on are it is characterised in that include following step
Suddenly：
(1) build the ligand-receptor complex molecular structure of flavone compound and androgen receptor；
(2) dynamics simulation is carried out to molecule ligand-receptor complex molecular structure；
(3) set up analog result and distinguish model；
(4) analog result is judged according to model：If compound is located at active region, judge that compound is anti-for having
Male activity；If compound is located at non-viable regions, judge compound for the male activity of nonreactive；If compound is located at confusion region
Domain, then carry out step 5 and six；
(5) in analog result, part, when A ring has methoxyl group and receptor is less than setting value in the hydrogen bond quantity that part is formed, judges
Judge compound for the male activity of nonreactive；
(6) receptor and part movement locus are observed, if the movement locus of part have had been detached from the combined mouth of androgen receptor
Bag, judges the male activity of compound nonreactive；If receptor " mousetrap " phenomenon after simulation process terminates, judge chemical combination
Thing has anti-male activity；
(7) as compound is all judged as the male activity of nonreactive through step 5 and six, then judge that compound, for the male activity of nonreactive, is otherwise sentenced
Seco compound is to have anti-male activity；
(8) CoMSIA forecast model is set up to the compound judging to have anti-male activity, prediction has anti-male activity chromocor compound
Active size.
2. according to claim 1 based on molecular dynamics simulation screening flavone compound anti-hero activity methods, it is special
Levy and be：In described step 1, the structure of ligand-receptor complex molecular structure adopts following steps：Build flavone compound
Molecular structure and androgen receptor initial state structure, carry out energy-optimised, and give Gasteiger-Huckel electric charge；Using
Part is respectively 0.5 and 0, chooses and dock to accessing receptor file, range threshold and the coefficient of expansion by the software of Sybyl7.3
Divide highest conformation as initial configurations, it is merged with receptor, form complex.
3. according to claim 2 based on molecular dynamics simulation screening flavone compound anti-hero activity methods, its
It is characterised by：The initial state structure of described androgen receptor adopts the aminoacid sequence file of androgen receptor, imports Swiss-
In the Model webserver, then Blast search is carried out for template with the albumin crystal structure of ER α initial state.
4. it is based on molecular dynamics simulation screening flavone compound anti-hero activity methods, its feature according to claim 1
It is：Carry out dynamics simulation in described step 2, carried out using GROMACS software, all give CHARMM27 to part and receptor
The force field parameter in the field of force, wherein receptor carries for software, and the force field parameter of part is given by Swiss-Param；To be entirely
System is put in the model cube body box being occupied by TIP3P hydrone, and the beeline apart from box border for the complex is received for 1
Rice, adds sodium ion or chloride ion to ensure the charge balance of system；Realize whole system with steepest descent method and conjugate gradient method
Energy convergence, then system is warming up to 300K and maintains always, and gives 1 normal atmosphere；Constraint receptor protein is laggard
The molecular dynamics simulation of row 50ps, finally revocation constraint is simulated.
5. according to claim 4 based on molecular dynamics simulation screening flavone compound anti-hero activity methods, it is special
Levy and be：In described dynamics simulation, electric interactions use particle mesh Ewald algorithm, and Van der Waals force is with 1 nanometer
Truncation radius, step-length 2fs of simulation, a system carries out the simulation of 20ns.
6. according to claim 1 based on molecular dynamics simulation screening flavone compound anti-hero activity methods, it is special
Levy and be：Described analog result is distinguished model foundation and is adopted following steps：Choose 48 kinds of typical flavonoids as screening collection, structure
Build 48 flavone-androgen receptor compounds, system carries out molecular dynamics simulation, body using Gromacs after pretreatment
System maintains 1atm, and truncation radius are set toDynamics simulation step-length is 2fs, and every 2ps preserves a conformation, and each system is entered
The dynamics simulation of row 20ns；Then root-mean-square-deviation analysis is carried out to H12, the H12 having the compound of anti-male activity protects in 8ns
It is fixed to keep steady, and the H12 of other systems is always maintained at fluctuating；H12 is imported R language in the root-mean-square-deviation of 8～20ns, obtains area
Sub-model.
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| CN110610745A (en) * | 2019-09-24 | 2019-12-24 | 南京大学 | Identification method of mixed mimetic and antiestrogen interferent based on enhanced sampling molecular dynamics simulation |
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