CN106389403B - Application and screening technique of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase - Google Patents
Application and screening technique of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase Download PDFInfo
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Abstract
The invention belongs to fields of biomedicine, are preparing application and screening technique on the drug for inhibiting S adenosylmethionine decarboxylase more particularly, to small molecule covalency inhibitor.A kind of small molecule covalency inhibitor, structural formula are as follows:Wherein R1 can be phenyl or aniline or benzamide or its substituted-phenyl group, methyl or ethyl, furans and its substituent group, pyrroles and its substituent group, pyridine and its substituent group etc.；The inhibitor further includes the pharmaceutically acceptable salt containing chemical structure shown in general formula I.The method for screening the small molecule covalency inhibitor of S adenosylmethionine decarboxylase to delete 68 residue of pyruvoyl in S adenosylmethionine decarboxylase crystal structure, and optimizes, the albumin crystal structure after being optimized in Rosetta software；The small molecule structure obtained with search carries out docking calculating using AutoDockVina software, screens to calculated result, is sorted according to marking, and screening obtains small molecule covalency inhibitor.
Description
Technical field
The invention belongs to fields of biomedicine, inhibit S- adenosine first sulphur in preparation more particularly, to small molecule covalency inhibitor
Application and screening technique on the drug of propylhomoserin decarboxylase.
Background technique
For a long time, in clinical and basic research, small molecule compound is widely used as drug or regulatory molecule, is used for
Treat disease or research biosystem.These small molecule compounds, can in a manner of covalently or non-covalently and target proteins into
Row combines.But since the researcher of early stage worries that covalent compound has biggish (" off-target ") effect of missing the target,
Very big side effect is caused, therefore in the screening of past rational drug and designing, covalent compound is usually avoided by.Also it is positive because
Docking (docking) in this way, past computer-aided screening method, to be substantially all for non-covalent compound carries out excellent
Change, for screening, the combination of Design and optimization and evaluation non-covalent compound and protein.However, hair is studied in summary in recent years
Existing, in the small molecule compound drug clinically used, nearly 1/3 drug is covalent compound, that is, passes through covalent mechanism
(intermediate state or final form), is combined with target proteins.This kind of covalent compound drug includes aspirin, Pan Nixi
Woods, phosphonomycin etc..Therefore, in recent years, many software for calculation and method are improved, for being total to for protein target
The screening and optimization of valence compound (drug or regulatory molecule), such as DOCKovalent, CovalentDock, CovDock,
DOCKTITE etc..But these methods are directed to the calculating that very complicated covalent bond is formed, and prediction result is also not too much
It is ideal.Wherein, DOCKovalent is the calculating side that currently the only success guiding experiment screens covalency inhibitor
Method.
Polyamines (polyamines) is a kind of positively charged cation micro molecule generated from amino acid metabolism, in all lifes
All exist in object, it is all indispensable to cell growth, differentiation, survival and natural biological function etc..The more positive charges of polyamines band
Characteristic, enable them to make by forming electrostatic with negatively charged large biological molecule (DNA, RNA, protein, cell membrane etc.)
With to regulate and control very extensive biological process, including chromosome knob is configured to, DNA is synthesized and stabilization, DNA replication dna, transcription
It is generated with translation, protein phosphorylation, ribosomes, ion channel and regulation, the radicals scavenging of film surface receptor etc..Natural
There are many kinds of polyamines.In mammals, there are three types of naturally occurring, i.e. putrescine (putrescine), spermidine (essence
Amidine), spermine. (spermine), they are essential to mammal normal growth and development.Since polyamines has important life
Object function, Intracellular levels are by stringent regulation.In the cell (such as tumour cell) quickly bred, polyamine level
It can rise and lack of proper care.Polyamine level increases, and accelerates along with cell Proliferation, apoptosis is reduced and tumor-infiltrated related to transfer
Expression raising of gene etc..Therefore, the regulation of polyamines becomes an important means in oncotherapy and medicament research and development.
S adenosylmethionine decarboxylase (AdoMetDC) is the key enzyme synthesized in polyamines body, for spermine and essence
The synthesis of amidine is most important, because the aminopropyl of spermine and spermidine derives from the decarboxylic reaction of AdoMetDC.Therefore, it synthesizes
AdoMetDC inhibitor inhibits the generation of spermine and spermidine, is a currently very popular oncotherapy approach.Meanwhile by
It is also required to maintain normal polyamine level in pathogenic microorganism, therefore AdoMetDC inhibitor also becomes for pathogenic microorganism
One important drugs target.
Currently, the inhibitor MGBG (mitoguazone) of AdoMetDC has been used for the treatment of the anti-leukocythemia in clinic and cancer
The chemotherapy ancillary drug of disease.But MGBG will lead to serious injury of mitochondria, therefore toxic side effect is very big.The suppression of AdoMetDC
Formulation C GP 48664 (SAM486A) comes into I phase and II phase clinical assessment.Therefore, it develops with more preferable effect
AdoMetDC new inhibitor is of great significance and is worth.
In our early-stage study (Scientific Reports, 2015, vol.5:10754), we have proposed one
The screening strategy of the non-covalent inhibitor of a S-adenosylmethionine AdoMetDC.By by active AdoMetDC (adenosine first sulphur
Propylhomoserin decarboxylase) a substrate binding pocket crucial unnatural amino acid Pyruvate68, sport Ser (serine),
We verify the combination conformation that can predict non-covalent inhibitor, and are used for the screening of non-covalent inhibitor.Meanwhile Wo Menfa
It is existing, the combination conformation of covalency inhibitor, can also be relatively good predicted, but due to small molecule covalent groups and Ser68
Between there are space collisions, so covalent groups have biggish deviation.
Summary of the invention
Based on this, the present invention provides the drug that small molecule covalency inhibitor inhibits S adenosylmethionine decarboxylase in preparation
On application and screening technique.
Technical solution of the present invention are as follows:
A kind of application of small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, this is small
The structural formula of molecule inhibitor are as follows:
Wherein: R1Can for phenyl or aniline or benzamide or its substituted-phenyl group, methyl or ethyl, furans and its
Substituent group, pyrroles and its substituent group, pyridine and its substituent group etc.；The inhibitor further includes containing change shown in general formula I
Learn the pharmaceutically acceptable salt of structure
The structural formula of the further preferred small molecule covalency inhibitor are as follows:
The small molecule commodity label are as follows: MCULE-4717492978 (http://zinc.docking.org/
substance/4387691)
A method of the small molecule covalency inhibitor of screening S adenosylmethionine decarboxylase, the method includes following
Step:
1) based on the crystal structure of S adenosylmethionine decarboxylase, by S adenosylmethionine decarboxylase crystal knot
68 residue of pyruvoyl in structure is deleted, and is optimized in Rosetta software, the albumin crystal structure after being optimized；
2) small molecule of the search for docking, small molecule compound library come from ZINC Interworking Data library, search for small molecule, clothes
It is engaged in after device return search result, obtains corresponding small molecule structure；
3) small molecule structure that albumin crystal structure and step 2) search after optimizing the step 1) obtain utilizes
AutoDockVina software carries out docking calculating, obtains docking calculated result；
4) calculated result that step 3) obtains is screened, is sorted according to marking, screening obtains small molecule and covalently inhibits
Agent；
Complete application of the method in the covalency inhibitor of screening S adenosylmethionine decarboxylase.
The step 2) searches for small molecule condition are as follows: 1. SMILES expression formula: C (=O) NN, and selects
" substructure " minor structure, to search for the molecular structure for containing above-mentioned group；2. molecular weight is greater than 200 and less than 400；③
Lipid≤3.5；4. rotatable key is more than or equal to 3, and is less than or equal to 9；5. hydrogen bond donor is more than or equal to 2, and is less than
Equal to 10；6. hydrogen bond receptor is more than or equal to 2, and is less than or equal to 10.
Step 4) the screening conditions include: 1. covalent bond atom i.e. NH in SMILES expression formula2In N position,
Less than 1 angstrom at a distance from the covalent N atom site after the covalent O atom of Pyr68 in mother crystal structure or inhibitor covalent bond；
2. the docking marking of the conformation is less than or equal to -8.0.
The method also includes spectroscopic methodologies and efficient liquid-phase chromatography method detection small molecule to S-adenosylmethionine decarboxylation
Whether inhibiting effect, verifying small molecule covalency inhibitor and the S adenosylmethionine decarboxylase of enzyme are covalently bound.
The spectroscopic methodology be small molecule mixed with S adenosylmethionine decarboxylase after 37 DEG C altogether incubation 30min after, add
It is detected after adding substrate methionine to react 5min, DMSO is solvent control, S-adenosylmethionine inhibitor mitoguazone
For positive control.
The efficient liquid-phase chromatography method instrument is Waters e2695, and pillar is Waters C18 reversed-phase column, institute
State reversed column be 5um, 4.6x250mm, 30 DEG C of column temperature, mobile phase 0.01mol/L ammonium formate: methanol=97:3, it is described
0.01mol/L ammonium formate pH is 3.5, flow velocity 0.5mL/min, Detection wavelength 254nm；Before loading, 9 times of volumes of reaction system are added
Methanol terminate reaction, 12000g be centrifuged 10min remove denaturation albumen after, take Supernatant samples to be analyzed, pass through detection bottom
The consumption of object methionine, inhibiting effect of the verifying small molecule to S adenosylmethionine decarboxylase.
Whether the verifying small molecule covalency inhibitor and S adenosylmethionine decarboxylase are covalently bound specific sides
Method is that addition substrate methionine opens after small molecule covalency inhibitor is incubated for different time with S adenosylmethionine decarboxylase
Dynamic catalysis reaction, terminates the consumption of reaction detection substrate after 10min, and the incubations different time is 0min, 30min, 60min,
90min。
The drug pocket of S adenosylmethionine decarboxylase used in the method, it is characterised in that: with S- adenosine
Based on the crystal structure of methionine decarboxylase, after the 68th pyruvoyl group in AdoMetDC crystal structure is deleted, with
Substrate methionine binding pocket forms the drug screening and design that widened binding pocket is S adenosylmethionine decarboxylase
Pocket.
The invention has the advantages that
1, the covalency inhibitor that the present invention screens acts on S adenosylmethionine decarboxylase obvious；
2, the method for the present invention is easy to operate, does not need to dock existing small molecule algorithm progress complex modifications, and effect is good
Good, this method is suitable for quickly carrying out the screening and design of covalency inhibitor；
3, the method for the present invention and other prediction technique ratios have suitable or better prediction effect.
4, calculating sifting method of the invention modifies docking algorithm due to not needing the difference according to experimental system, institute
There is wider applicability, can be adapted for all covalent inhibition compared with other known covalency inhibitor screening technique
The screening of agent and design system；The docking calculation method for having developed perfect numerous non-covalent inhibitor can be utilized extensively,
Therefore the screening, optimization and discovery of covalency inhibitor can be greatly accelerated.
5, experimental subjects of the invention is source of people AdoMetDC, but same due to having between the AdoMetDC of separate sources
Source property, therefore our general AdoMetDC that can act on other non-source of people of inhibitor, and others AdoMetDC
Homologous protein enzyme.
Detailed description of the invention
Fig. 1: activity inhibition contrast effect of the small molecule covalency inhibitor of the present invention to AdoMetDC.
Inhibiting effect of Fig. 2: HPLC analysis this small molecule of result verification to AdoMetDC；
Fig. 3: small molecule covalency inhibitor of the present invention and AdoMetDC are incubated for influence of the different time to rejection ability altogether；
Fig. 4: small molecule covalency inhibitor molecular structure of the present invention；
Fig. 5: small molecule covalency inhibitor of the present invention docks conformation with AdoMetDC's
Specific embodiment
The present invention is further illustrated below with reference to embodiment, but the scope of protection of present invention is not limited to implement
The range of example statement.
Embodiment 1
It 1) is 3DZ5's by PDB ID based on the crystal structure of S adenosylmethionine decarboxylase (AdoMetDC)
Pyr68 residue in AdoMetDC crystal structure is deleted, and is optimized in Rosetta, the SCAR albumin crystal after being optimized
Structure；
2) the small molecule compound library for docking comes from and docks number with ZINC (http://zinc.docking.org)
According to library, small molecule search condition are as follows: 1. SMILES expression formula: CONN, and " substructure " minor structure is selected, contained with search
There is the molecular structure of above-mentioned group；2. molecular weight is greater than 200 and less than 400；③xLogP≤3.5；4. rotatable key is more than or equal to
3, and it is less than or equal to 9；5. hydrogen bond donor is more than or equal to 2, and is less than or equal to 10；6. hydrogen bond receptor is more than or equal to 2, and is less than or equal to
10, after server returns to search result, obtain the structure of corresponding small molecule；
3) by the step 1) optimization after structure and step 2) search small molecule structure using AutoDockVina into
Row docking calculates, and obtains docking calculated result；
4) calculated result that step 3) obtains is screened, screening conditions include: 1. covalently to tie in SMILES expression formula
Close atom (NH2In N) position, with the covalent O atom of Pyr68 in mother crystal structure (or being total to after inhibitor covalent bond
Valence N atom) position distance less than 1 angstrom；1. the docking marking of the conformation is less than or equal to -8.0, sorted according to marking, selection can
Buy compound be used for experiment screening, obtain small molecule covalency inhibitor MCULE-4717492978 (http: //
Zinc.docking.org/substance/4387691) (the entitled retailer's number of small molecule)；The small molecule covalently inhibits
The structural formula of agent are as follows:
Embodiment 2
Using the method for patent (ZL201410530672.3), We conducted AdoMetDC activity rating, spectroscopic methodology inspections
1 small molecule covalency inhibitor of embodiment that the step 4) obtains is surveyed to the activity inhibition of AdoMetDC, small molecule with
After AdoMetDC mixing after 37 degree are incubated for 30min altogether, being detected after adding substrate reactions 5min, DMSO is solvent control,
AdoMetDC inhibitor MGBG (mitoguazone) is positive control, and the result is shown in Figure 1, this small molecule covalency inhibitor all compares MGBG
There is better rejection ability；
Embodiment 3
1 small molecule of embodiment is verified by the consumption of detection substrate AdoMet using high performance liquid chromatography (HPLC) method
To the inhibiting effect of AdoMetDC.HPLC instrument be Waters e2695, pillar be Waters C18 reversed-phase column (5um,
4.6x250mm), 30 degree of column temperature, mobile phase 0.01mol/L ammonium formate (pH 3.5): methanol=97:3, flow velocity 0.5mL/min, inspection
Survey wavelength 254nm.Before loading, the methanol that 9 times of volumes are added terminates reaction, after 12000g is centrifuged the albumen that 10min removes denaturation,
It takes Supernatant samples to be analyzed, as a result sees Fig. 2, after small molecule mixes incubation 30min with AdoMetDC at 37 degree as shown in Figure 2,
Reaction, and the consumption of detection substrate are terminated after adding substrate reactions 0min, 5min or 10min.Fig. 2 shows that this small molecule is total
Valence inhibitor can inhibit the consumption of substrate (main peak is higher, indicates that amount of substrate is more in detection architecture)；
Embodiment 4
Using HPLC method, demonstrating 1 small molecule covalency inhibitor of embodiment is all, general covalently bound with AdoMetDC
Small molecule covalency inhibitor and AdoMetDC are incubated for the different times (0min, 30min, 60min, 90min) and add substrate afterwards
AdoMet starting catalysis is reacted, and the consumption of reaction detection substrate is terminated after 10min.(Fig. 3) is with total incubation time as the result is shown
Extension, small molecule have higher rejection ability, with the extension of incubation time, the activity (open circles) of AdoMetDC does not have
The rejection ability of significant changes, non-covalent inhibitor MGBG (hollow square) does not also increase.And we have found that 3 small molecules
Inhibitor, longer with AdoMetDC incubation time, inhibitory effect is better (substrate remnants percentage is bigger).Substrate remnants percentage
Refer to the ratio of the substrate peak area of the sample and the peak area of individual Substrate controls sample.The ratio is bigger, shows bottom
Object residual volume is more, and the substrate of enzymic catalytic reaction consumption is fewer, i.e., apparent enzymatic activity is weaker.
The molecular structure of small molecule covalency inhibitor of the present invention is shown in Fig. 4.- C (=O)-NH-N*H2 is covalent groups, and N* is
Covalent bond atom.Small molecule covalency inhibitor of the present invention is shown in Fig. 5 with the conformation of docking of AdoMetDC, and wherein M8M is PDB structure
AdoMetDC covalency inhibitor in 3DZ5.The covalent bond atom N* of this small molecule is respectively positioned on being total to for covalency inhibitor M8M
Valence N atom site (spherical point shows its atomic radius), therefore covalent bond can be formed with the O atom of Pyr68.The key of surrounding
Interaction residue is indicated in M8M corresponding diagram.
Embodiment 5
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
Embodiment 6
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
Embodiment 7
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
Embodiment 8
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
Embodiment 9
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
Embodiment 10
Application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the micromolecular inhibitor are as follows:
The above embodiments are only the preferred technical solution of the present invention, and are not construed as limitation of the invention, this Shen
Please in embodiment and embodiment in feature in the absence of conflict, can mutual any combination.Protection model of the invention
The technical solution that should be recorded with claim is enclosed, the equivalent replacement side of technical characteristic in the technical solution recorded including claim
Case is protection scope.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.
Claims (1)
1. application of the small molecule covalency inhibitor on the drug that preparation inhibits S adenosylmethionine decarboxylase, feature exist
In the structural formula of the small molecule covalency inhibitor are as follows:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110444250A (en) * | 2019-03-26 | 2019-11-12 | 广东省微生物研究所（广东省微生物分析检测中心） | High-throughput drug virtual screening system based on molecular fingerprint and deep learning |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968804A (en) * | 1988-07-07 | 1990-11-06 | Ciba-Geigy Corporation | Bipyridine compounds |
| US5376685A (en) * | 1988-03-25 | 1994-12-27 | Ciba-Geigy Corporation | Arylhydrazones using as SAMDC inhibitors |
| US5840911A (en) * | 1995-01-26 | 1998-11-24 | Novartis Ag | Imidazole derivatives, their preparation and their use as S-adenosylmethionine decarboxylase (=SAMDC) inhibitors |
-
2016
- 2016-04-22 CN CN201610257321.9A patent/CN106389403B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5376685A (en) * | 1988-03-25 | 1994-12-27 | Ciba-Geigy Corporation | Arylhydrazones using as SAMDC inhibitors |
| US4968804A (en) * | 1988-07-07 | 1990-11-06 | Ciba-Geigy Corporation | Bipyridine compounds |
| US5840911A (en) * | 1995-01-26 | 1998-11-24 | Novartis Ag | Imidazole derivatives, their preparation and their use as S-adenosylmethionine decarboxylase (=SAMDC) inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110444250A (en) * | 2019-03-26 | 2019-11-12 | 广东省微生物研究所（广东省微生物分析检测中心） | High-throughput drug virtual screening system based on molecular fingerprint and deep learning |
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