CN113398121A - Application of virtually screened compound as integrin protein alpha v beta 3 antagonist and application of virtually screened compound in preparation of antitumor drugs - Google Patents
Application of virtually screened compound as integrin protein alpha v beta 3 antagonist and application of virtually screened compound in preparation of antitumor drugs Download PDFInfo
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Abstract
The invention provides application of a virtual screening compound as an integrin protein alpha v beta 3 antagonist and application of the virtual screening compound in preparing an anti-tumor medicament, wherein the virtual screening compound has a structure shown in a formula I, a formula II or a formula III. The invention tests the binding activity of the Surface Plasmon Resonance (SPR) detection of the three small molecular compounds of the formulas I to III obtained by screening, and the results show that the K of the interaction of the compounds of the formulas I, II and III and the integrin protein alpha v beta 3DThe values were 1.58X 10M, respectively‑7，2.72×10M‑7，9.64×10M‑7(ii) a Shows that the protein has high binding activity with alpha v beta 3. The evaluation test of the anti-tumor active cells shows that the three compounds obtained by virtual screening have obvious anti-tumor activity aiming at various tumor cells.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to application of a virtual screening compound as an integrin protein alpha v beta 3 antagonist and application thereof in preparation of antitumor drugs.
Background
Integrin proteins are the major cell adhesion mediators on the cell surface. Especially, integrin α v β 3 has been extensively studied and focused as a target for cancer therapy. As it mediates multiple angiogenic processes during tumor development. The peptide sequence Arg-Gly-asp (RGD) is present in many endogenous integrin ligands, such as fibronectin, vitronectin and extracellular matrix (ECM) related proteins, and has also been widely used as a targeting vector for therapy in the field of tumor diagnosis, and drugs such as cyclic RGD peptide cilentitide have entered clinical trials for the treatment of various cancers in terms of tumor therapy, but unfortunately, the current drugs directed against RGD have failed to show true therapeutic benefit in clinical trials. Recent research advances in other novel peptide sequence peptidomimetics and small molecules, however, have shown that RGD-based targeted therapies are not the end-point of the study. At present, based on the intensive research of the combination mode of the compounds and the biological effect after combination of the compounds and the avb3, the advantages of the compounds are shown, and the compounds are very expected to be used as a new treatment means to be applied to clinic in the future.
Disclosure of Invention
The invention aims to provide application of a virtual screening compound as an integrin protein alpha v beta 3 antagonist and application thereof in preparing antitumor drugs, and the novel integrin protein alpha v beta 3 antagonist has high binding activity and antitumor activity with protein alpha v beta 3.
The invention provides an application of a virtual screening compound in integrin protein alpha v beta 3 antagonist, wherein the virtual screening compound has a structure shown in a formula I, a formula II or a formula III:
preferably, the virtual screening compound is obtained by generating a molecular fingerprint descriptor through Morgan2, establishing a screening model by using a machine learning model RF and an SVM algorithm, then carrying out primary screening from a SPECS database, and then carrying out continuous screening by using molecular docking.
The invention provides an application of a virtual screening compound in preparing an anti-tumor medicament, wherein the virtual screening compound has a structure shown in a formula I, a formula II or a formula III:
preferably, the tumor is prostate cancer, glioma, ovarian cancer or melanoma.
The invention aims to provide an application of a virtual screening compound as an integrin protein alpha v beta 3 antagonist, wherein the virtual screening compound has a structure shown in a formula I, a formula II or a formula III. The invention tests the binding activity of the Surface Plasmon Resonance (SPR) detection of the three small molecular compounds of the formulas I to III obtained by screening, and the results show that the K of the interaction of the compounds of the formulas I, II and III and the integrin protein alpha v beta 3DThe values were 1.58X 10M, respectively-7，2.72×10M-7， 9.64×10M-7(ii) a Shows that the protein has high binding activity with the alpha v beta 3. The evaluation test of the anti-tumor active cells shows that the three compounds obtained by virtual screening have obvious anti-tumor activity aiming at various tumor cells.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 shows the results of docking a compound of formula I with an α v β 3 receptor molecule;
FIG. 2 shows the docking of a compound of formula II with an α v β 3 receptor molecule;
FIG. 3 shows the docking of a compound of formula III with an α v β 3 receptor molecule;
FIG. 4 is a graph of coupled sensor signals of compounds of formula I at different concentrations on a chip surface;
FIG. 5 is a graph of a kinetic fit of compounds of formula I at various concentrations on a chip surface;
FIG. 6 is a graph of coupled sensor signals of compounds of formula II at different concentrations on a chip surface;
FIG. 7 is a graph of a kinetic fit of compounds of formula II at various concentrations on a chip surface;
FIG. 8 is a graph of coupled sensor signals of compounds of formula III at different concentrations on a chip surface;
FIG. 9 is a graph of a kinetic fit of compounds of formula III at various concentrations on a chip surface;
FIG. 10 is a graph of the antitumor activity of compounds of formula I against PC-3 cells, DU-145 cells, HUVEC-T1 cells, and U87 cells;
FIG. 11 is a graph of the antitumor activity of compounds of formula I against WM115 cells, OVCAR-4 cells, 22RV1 cells and HMEC-1 cells;
FIG. 12 is a graph of the antitumor activity of the compounds of formula II on PC-3 cells, DU-145 cells, HUVEC-T1 cells, and U87 cells;
FIG. 13 is a graph of the antitumor activity of compounds of formula II against WM115 cells, OVCAR-4 cells, 22RV1 cells and HMEC-1 cells;
FIG. 14 is a graph of the antitumor activity of the compound of formula III against PC-3 cells, DU-145 cells, HUVEC-T1 cells, and U87 cells;
FIG. 15 is a graph of the antitumor activity of compounds of formula III against WM115 cells, OVCAR-4 cells, 22RV1 cells and HMEC-1 cells.
Detailed Description
Virtual screening
The invention discloses a small molecule inhibitor of an alpha v beta 3 receptor based on a method of machine learning and molecular docking. α v β 3 integrin inhibitors (1337 molecules) were first downloaded from the pubchem database, with the Decoy dataset generated. Split into a training set (962 molecules), a test set (241 molecules), a validation set (134 molecules), and an external test set (182 molecules) downloaded from chembl. Molecular fingerprint descriptors were generated by Morgan 2. And then, establishing a screening model by adopting a machine learning model RF and an SVM algorithm.
The screening model was used to perform a preliminary screening of 35 ten thousand small molecules from the SPECS database, followed by FRED molecular docking and Discovery Studio molecular docking using α v β 3 crystal structures (1L5G and 6MK0) downloaded from PDB. The present invention defines a well defined active pocket by the original ligand in the crystal structure, followed by docking of the structure-pretreated compound into the active pocket. Each conformation of the compounds was then ordered using molecular docking scoring and the docked conformations and interaction forces were analyzed.
In vitro screening
The interaction condition of the compound obtained by virtual screening and the integrin receptor protein in the solution is detected by a Surface Plasmon Resonance (SPR) technology.
Laboratory apparatus and reagent
Other reagents are all purchased from chemical reagents of national drug group, Inc.
Experimental methods
Surface plasmon resonance Biacore 8K was used to analyze the interaction of small molecule compounds and integrin proteins α v β 3. The system temperature was first set at 25 ℃ and the flow rate was set at 5. mu.L/min, and the flow was measured through PBS buffer until the baseline stability channel 2(FC-2) was set as the coupled protein channel and channel 1(FC-1) was set as the control channel, and the presence of non-specific binding reactions was detected for background subtraction.
Selection of pretreatment-coupling pH
Without activating the chip surface, the integrin α v β 3 protein sample was dissolved in sodium acetate buffers of different pH values (pH 4, 4.5, 5) to charge them with different amounts, and the integrin protein sample was flowed over the chip surface at a flow rate of 5 μ L/min, and after determining the appropriate pH conditions by the integrin-chip binding profile, 20 μ L of 0.1M NaOH eluent was injected to wash off the protein adsorbed on the chip surface
Conjugation of integrin α v β 3 proteins
The CM5 chip was selected and the coupling of proteins was performed according to the amino coupling protocol as follows
(1) Activation (Activation) 35. mu.L of NHS/EDC mixture (0. IM NHS and 0.4MEDC, mixed at 1:1 volume ratio before use, used immediately) was injected at a flow rate of 5. mu.L/min to activate carboxyl groups of dextran on the chip surface
(2) Coupling (Immobilisation) 50. mu.L of a 50. mu.g/mL integrin α v β 3 protein solution was prepared in buffer at the pH determined in the pretreatment, and injected at a flow rate of 5. mu.L/min for 7 minutes
(3) Blocking (Blocking) the protein was coupled by Blocking with 15. mu.L of 1M ethanolamine hydrochloride for 3 minutes.
Binding experiments
The compounds to be tested were dissolved in DMSO and made to a concentration of 10mM, and then serially diluted with PBD and injected at a flow rate of 5. mu.L/min for 5 minutes for preliminary binding analysis.
Chip regeneration
5u L4M guanidine hydrochloride rinse, 5u L/min flow rate injection for 2 minutes.
TABLE 1 molecular docking scoring of α v β 3 Small molecule antagonists
FIGS. 1 to 3 show the results of the docking of compounds of formula I, formula II and formula III with α v β 3 receptor molecules;
FIG. 1 shows the results of molecular docking of the compound of formula I with α v β 3 receptor, and it can be seen from FIG. 1 that the compound of formula I can bind well to α v β 3 receptor. Can form hydrogen bonds with a plurality of amino acids, such as Try122, Arg214 and Asn215, and form conjugate bonds with Trp178 and Ala 149.
FIG. 2 shows the docking results of the compound of formula II with α v β 3 receptor molecules, and it can be seen from FIG. 2 that the compound of formula II can bind well to α v β 3 receptor. Can form hydrogen bonds with a plurality of amino acids, such as Arg214, Asp148, Glu123 and Lys119, and form conjugate bonds with Ala218, Ala149 and Arg 214.
FIG. 3 shows the docking results of the compound of formula III with α v β 3 receptor molecules, and it can be seen from FIG. 3 that the compound of formula III binds well to α v β 3 receptor. Can form hydrogen bonds with a plurality of amino acids, such as Arg216, Arg214, Asp179 and Lys119, and form conjugate bonds with Ala218 and Ala 149.
Binding assays
In the SPR experiment, in order to examine whether a compound binds to integrin protein, a direct method is used to determine that when a solution of an analyte compound flows onto the surface of a chip, the analyte binds to the conjugates (proteins) on the surface of the chip, causing a change in the quality of the chip surface and thus a change in resonance signal. The results of the interaction of integrin α v β 3 protein with small molecule compounds are presented as sensorgrams, with the ordinate representing the level of small molecule compound binding to the protein, as shown in fig. 4-6, recorded continuously as a response signal (RU), and the abscissa representing time. In FIGS. 4 to 6, the left image is a coupling sensorgram of a compound on the surface of a chip, and the right image is a kinetic fitting curve.
Kinetic analysis
In addition to obtaining information on the presence or absence of binding between biomolecules, SPR analysis can also obtain various kinetic information on interactions between molecules, including dissociation equilibrium constant (K)D)。
The experimental results of FIGS. 4-6 show that the compounds of formula II, III and I interact with protein alpha v beta 3DThe values were 2.72X 10M, respectively-7，9.64×10M-7， 1.58×10M-7. The compounds show high binding activity with protein alpha v beta 3 and are possible to be potential micromolecule antagonists of integrin protein alpha v beta 3.
Evaluation of antitumor Activity
1) Tumor cell recovery culture
Removing frozen tumor cells (cells of prostate cancer, ovarian cancer and the like) from liquid nitrogen, quickly dissolving at 37 ℃, adding into 5mL of corresponding medium containing FBS, centrifuging for 5 minutes at 300g, collecting precipitates, re-suspending with the corresponding medium, fully mixing, adding into a 24-hole cell culture dish, supplementing the medium to 2mL of the total volume per hole at 37 ℃, culturing to reach about 90% of confluence degree, and performing subculture amplification or counting plating.
2) Tumor cell inoculation
When the tumor cells are cultured to be passable, the cells are digested by pancreatin to prepare single cell suspension. After cell counting, cell concentration was adjusted to 1.2 × 10 using the corresponding medium4cells/ml, adding 90ul of the mixed solution into a 96-well plate, incubating at 37 ℃ for 30 minutes, adding corresponding culture, culturing overnight in a 37 ℃ cell culture box, and observing the morphology and the confluence degree of tumor cells.
3) Compound formulation and dilution
After overnight tumor cell culture, compound gradient dilutions were prepared and added to the culture system.
Stock solutions (100mM) of compounds dissolved in DMSO were dissolved well at room temperature and, if insoluble, were re-observed by sonication for 5 minutes until dissolved.
Adding 20ul DMSO into No. 2-9 holes in a 96-hole V-shaped compound dilution plate respectively, adding 30ul stock solution into 1 hole, placing the compound dilution plate on a vibration mixer, transferring 10ul liquid from the No. 1 hole to add the No. 2 hole, blowing, beating, vibrating, mixing uniformly, transferring 10ul liquid from the No. 2 hole to the No. 3 hole, vibrating, blowing, mixing uniformly, sequentially repeating … until transferring 10ul liquid from the No. 8 hole to the No. 9 hole, blowing, vibrating, mixing uniformly, and preparing 1000x gradient dilution stock solution. [ note: DMSO readily absorbed moisture from the air, and after handling, the plates were immediately diluted with a sealing film blocking compound, stored at 4 degrees celsius, and discarded after 1 week. When the moisture absorption type sealing film is used again, the sealing film is opened after the temperature reaches the room temperature, and the concentration inaccuracy caused by moisture absorption is avoided. "C (B)
And (3) taking a 96-hole sterile cell culture plate, adding 198ul of culture medium into a No. 1-9 hole in an ultra-clean workbench, transferring 2ul of stock solution to a No. 1-9 hole corresponding to the 96-hole sterile cell culture plate from a 1000x stock solution by using a microsyringe, shaking, blowing, beating and uniformly mixing to prepare a 10x stock solution. The stock solution needs to be prepared and used on the same day.
10ul of the 10 Xstock solution prepared on the day was added to the cell culture medium. Taking the compound of formula I (Cpd #19) as an example, it is shown in Table 2:
TABLE 2
4) Adding the drug to be tested
After observing that the adherent growth of the tumor cells is good, 10 μ L of the compound with the corresponding concentration is added according to the Plate map, and a 10x stock solution is prepared on the same day. Incubate at 37 ℃ for 72h with 5% carbon dioxide. Taking the structural compound (Cpd #19) of formula I as an example, the dosing arrangement is shown in table 3:
TABLE 3
Null-blank well. DMSO-wells to which DMSO was added. BEZ 235: add 2.5uM wells of BEZ 235. Staurosporine 1uM Staurosporine was added.
5) Chemiluminescence assay
And measuring the ATP level of the cells by adopting a chemiluminescence method, and further evaluating the cell viability. The specific operation is carried out according to the instruction, 50 mu LCTG solution is added after the culture is finished, the mixture is uniformly mixed, the cracking mixture is transferred to an ELISA plate, and after 5-10 minutes, chemiluminescence data is collected in an ELISA reader. The processed data were analyzed using Excel software and IC50 was calculated from the fitted pharmacodynamic curve of the chemiluminescent data using GraphPad Prism 7 software.
6) Control and quality control
The Z factor is used as a quality control index in the test. The Z' factor is defined by 4 parameters: mean (μ) and standard deviation (σ) of positive control (p) and negative control (n).
The calculation formula is as follows:
Z’factor＝1-(3*(σp+σn)/|(μp-μn)|)
the negative control group is an untreated group added with a solvent (DMSO); positive controls were supplemented with 2.5uM BEZ235 or 1uM Staurosporine.
Functional assays at the general cellular level Z' factor requires > 0.3; the quality control pass value Z' factor of the test is set to be > 0.5.
The anti-tumor activity of 3 compounds in the invention is detected by using 16 culture plates aiming at 8 tumor cells. The culture plate 1 is used for detecting the antitumor activity of the compound with the structure shown in the formula I and the formula III on human prostate cancer cells PC-3, wherein Z '(BEZ) ═ 0.71, Z' (Staurosporine) ═ 0.79; the culture plate 2 is used for detecting the antitumor activity of the compound with the structure shown in the formula II on human prostate cancer cells PC-3, wherein Z '(BEZ) ═ 0.78, Z' (Staurosporine) ═ 0.83;
the culture plate 3 is used for detecting the antitumor activity of the compound with the structure shown in the formula I and the formula III on human prostate cancer cells DU-145, wherein Z '(BEZ) ═ 0.79 and Z' (Staurosporine) ═ 0.83; the culture plate 4 is used for detecting the antitumor activity of the compound with the structure shown in the formula II on human prostate cancer cells DU-145, wherein Z '(BEZ) ═ 0.71, Z' (Staurosporine) ═ 0.78;
the culture plate 5 is used for detecting the activity of the structural compound shown in the formula I and the formula III on HUVEC-T1 of human umbilical vein endothelial cells, wherein Z '(BEZ) ═ 0.62 and Z' (Staurosporine) ═ 0.65; the culture plate 6 is used for detecting the activity of the compound with the structure shown in the formula II on HUVEC-T1 human umbilical vein endothelial cells, wherein Z '(BEZ) ═ 0.81, Z' (Staurosporine) ═ 0.83;
the culture plate 7 is used for detecting the antitumor activity of the structural compound shown in the formula I and the formula III on human glioma cells U87, wherein Z '(BEZ) ═ 0.55, Z' (Staurosporine) ═ 0.73; the culture plate 8 is used for detecting the antitumor activity of the structural compound shown as the formula II on human glioma cells U87, wherein Z '(BEZ) ═ 0.74 and Z' (Staurosporine) ═ 0.83;
the culture plate 9 is used for detecting the antitumor activity of the structural compounds shown in the formula I and the formula III on human melanoma cells WM115, wherein Z '(BEZ) ═ 0.69, Z' (Staurosporine) ═ 0.86; the culture plate 10 is used for detecting the antitumor activity of a compound with a structure shown in a formula II on human melanoma cells WM115, wherein Z '(BEZ) ═ 0.68 and Z' (Staurosporine) ═ 0.87;
the culture plate 11 is used for detecting OVCAR-4 antitumor activity of the structural compounds shown in formula I and formula III on human ovarian cancer cells, wherein Z '(BEZ) ═ 0.70, Z' (Staurosporine) ═ 0.85; the culture plate 12 is used for detecting OVCAR-4 antitumor activity of a compound with a structure shown in formula II, wherein Z '(BEZ) ═ 0.54 and Z' (Staurosporine) ═ 0.75;
the culture plate 13 is used for detecting the antitumor activity of the structural compound shown in the formula I and the formula III on human prostate cancer cells 22RV1, wherein Z '(BEZ) ═ 0.80, Z' (Staurosporine) ═ 0.83; the culture plate 14 is used for detecting the antitumor activity of the compound with the structure shown in the formula II on human prostate cancer cells 22RV1, wherein Z '(BEZ) ═ 077 and Z' (Staurosporine) ═ 0.81;
the culture plate 15 is used for detecting the activity of the compound with the structure shown in the formula I and the formula III on human microvascular endothelial cells HMEC-1, wherein Z '(BEZ) ═ 0.87, Z' (Staurosporine) ═ 0.93; the culture plate 16 is used for detecting the activity of the compound with the structure shown in the formula II on human microvascular endothelial cells HMEC-1, wherein Z '(BEZ) ═ 079 and Z' (Staurosporine) ═ 0.87.
Data on antitumor Activity
1) The anti-tumor activity of the compound with the structure shown in the formula I is shown in figures 10-11 (see the data in table 4), the figures 10-11 are the activity data of the compound with the structure shown in the formula I on various tumor cells, and as can be seen from figures 10-11, the compound with the structure shown in the formula I has obvious anti-tumor activity on prostate cancer PC-3, DU145 and 22RV1 cells, and has the highest tumor inhibition effect on melanoma cells WM 115. Human glioma cell U87 and ovarian cancer cell OVCAR-4 also have inhibitory effect. In addition, it also has inhibitory effect on vascular endothelial cell HUVEC-T11 and microvascular endothelial cell HMEC-1.
2) The anti-tumor activity of the compound with the structure shown in the formula II is shown in figures 12-13 (see the data in table 4), figures 12-13 are the activity data of the compound with the structure shown in the formula II on various tumor cells, and as can be seen from figures 12-13, the compound with the structure shown in the formula II has obvious anti-tumor activity on prostate cancer cells DU145 and has the best anti-tumor activity on the prostate cancer cells DU 145.
3) The anti-tumor activity of the compound with the structure shown in the formula III is shown in figures 14-15 (see data in table 4), figures 14-15 are activity data of the compound with the structure shown in the formula III on various tumor cells, and as can be seen from figures 14-15, the compound with the structure shown in the formula III has obvious difference on the anti-tumor activity of different tumor cells, wherein the anti-tumor activity on the prostate cancer enzalutamide drug-resistant cell line 22RV1 is optimal.
TABLE 4 antitumor Activity data for Compounds of formula I, formula II and formula III
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (4)
1. Use of a virtual screening compound for an integrin protein α ν β 3 antagonist, the virtual screening compound having a structure according to formula I, formula II or formula III:
2. the use according to claim 1, wherein the virtual screening compound is obtained by generating molecular fingerprint descriptors by Morgan2, building a screening model using machine learning model RF and SVM algorithms, performing a preliminary screening from a SPECS database, and continuing the screening using molecular docking.
3. The application of a virtual screening compound in preparing an anti-tumor medicament, wherein the virtual screening compound has a structure shown in a formula I, a formula II or a formula III:
4. the use according to claim 3, wherein the tumor is prostate cancer, glioma, ovarian cancer or melanoma.
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| WO2022170822A1 (en) * | 2021-02-10 | 2022-08-18 | 北京大学第一医院 | Indazole hydrazide compound and application thereof |
| CN113101287A (en) * | 2021-05-14 | 2021-07-13 | 北京大学第一医院 | Application of indazole hydrazide compound in preparation of anti-tumor angiogenesis medicine |
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