CN110718268B - Application of virtual screening in preparation of protein kinase inhibitor and pharmaceutical lead compound - Google Patents
Application of virtual screening in preparation of protein kinase inhibitor and pharmaceutical lead compound Download PDFInfo
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Classifications
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
- G16B15/20—Protein or domain folding
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/50—Molecular design, e.g. of drugs
Abstract
The invention belongs to the field of pharmaceutical chemistry, and provides application of virtual screening in preparation of protein kinase inhibitors and a pharmaceutical lead compound, wherein the screening method comprises the following steps: (1) obtaining candidate compounds by virtual screening; (2) And (3) detecting the in-vitro protein kinase activity and the anti-tumor cell proliferation activity of the candidate compound obtained in the step (1), and screening to obtain the target compound. The screening method of the invention obtains the target compound with inhibitory activity to CK2 and lung cancer cell A549, and the method has the advantages of time saving, labor saving, cost saving, high efficiency and the like.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a screening method of a protein kinase inhibitor and application of a drug lead compound in the protein kinase inhibitor or/and an anti-tumor proliferation drug.
Background
Protein kinase CK2 (Protein kinase CK 2) is a highly conserved serine/threonine protein kinase, has the biological characteristics of substrate protein diversification, can catalyze more than 300 protein substrates, and is involved in various cell regulation processes, including cell growth and proliferation, cell survival and apoptosis, embryo development and organ formation, transcriptional regulation and the like, and is a key regulator of many cell processes. It has been found that even modest down-regulation results in extensive cell death by apoptotic mechanisms when cells are stimulated by certain conditions resulting in forced down-regulation of CK2 levels in the nucleus. Thus, CK2 is an important class of anticancer therapeutic targets.
Currently, while most CK2 inhibitors belong to ATP-competitive inhibitors, this class of inhibitors is challenging in terms of their selectivity due to the high degree of conservation of the ATP active site in the protein kinase family. For example: CX-4945 entering the clinical phase II study, while described as having high selectivity, also inhibits at least twelve other nano-ICs 50 Kinase of value and is more effective against Clk2 than it inhibits CK 2. Therefore, we hope to develop CK2 allosteric inhibitors with high affinity by targeting non-ATP sites.
With the vigorous development of computer-aided drug design, the virtual drug screening effectively solves the problems of high cost and high risk in the traditional drug development process, becomes a complementary technology with high-throughput screening, and is an important method for discovering lead compounds and activity optimization thereof. Therefore, a rapid and efficient virtual screening method of the protein kinase inhibitor is established, and the method has important significance for the discovery of novel protein kinase allosteric inhibitor and the application of the novel protein kinase allosteric inhibitor in the aspect of anti-tumor proliferation.
Disclosure of Invention
The invention aims to provide a rapid and efficient screening method of a protein kinase inhibitor and application of a target compound in the protein kinase inhibitor or/and an anti-tumor drug.
The invention adopts the following technical scheme:
a method of screening for a protein kinase inhibitor comprising the steps of:
(1) Obtaining candidate compounds by a virtual screening method;
(2) And (3) carrying out biological activity screening on the candidate compound obtained in the step (1) to obtain the target compound.
According to the invention, the virtual screening in step (1) is preferably a virtual screening method based on a pharmacophore model and molecular docking;
preferably, the pharmacophore model construction method adopts Discovery Studio 4.0 software, and the molecular docking method adopts GOLD software.
According to the invention, the biological activity screening in step (2) is a kinase activity detection assay and an anti-tumor cell proliferation assay;
preferably, the kinase activity assay is ADP-Glo kinase activity assay and the anti-tumor cell proliferation assay employs Cell Counting Kit-8 (CCK-8).
As an embodiment, the screening method of the present invention comprises the steps of:
(S1.1) obtaining a three-dimensional structure of a protein kinase CK2 and inhibitor co-crystal from Protein data bank, retaining and setting an active pocket according to the bound inhibitor;
(S1.2) constructing a pharmacophore model based on receptor protein kinase CK2 by utilizing the three-dimensional structure of the protein kinase CK2 and the inhibitor eutectic obtained in the step S1.1, and carrying out preliminary screening on a small molecular compound library based on a matching degree value by using the pharmacophore model as a query to obtain a preliminary screening compound library;
(S1.3) according to the active pocket set in the step (S1.1), carrying out molecular docking and scoring sorting on the compound screened in the step S1.2 by using molecular docking software, further screening to obtain a fine screening compound library, and obtaining candidate compounds by evaluating the interaction mode of docking molecules and CK 2;
(S2) carrying out a kinase activity detection experiment and an anti-tumor cell proliferation experiment by using the candidate compound obtained in the step S1.3 to obtain a target compound.
According to the screening method of the invention, in the step S1.1, the three-dimensional structure of the protein kinase CK2 and the inhibitor is the three-dimensional structure of the protein kinase CK2 and the inhibitor in the existing protein database, or the three-dimensional structure of the protein kinase CK2 and the inhibitor in the existing protein database;
according to the screening method of the present invention, in step S1.2, the pharmacophore model construction method is as follows: constructing a pharmacophore model based on a receptor by using Discovery Studio 4.0, adopting a determined molecular substance active to the receptor and an inactive molecular substance, performing model verification by using a Screen Library module, obtaining a pharmacophore model containing 3-5 effective pharmacophore characteristic elements, and screening an alternative small molecular compound Library by using a matching degree value of more than 2.5-3.5 to obtain a primary screening compound Library.
Preferably, the small molecule compound library in step S1.2 is a library of ChemBridge fragments.
According to the screening method of the present invention, in step S1.3, the molecular docking procedure is preferably GOLD, and other molecular docking software may be used instead, for example: one or more of AutoDock vina, flexX or Glide;
preferably, when GOLD is used for dock scoring, a Goldscore scoring function is used;
preferably, the pool of fine screening compounds is preferably the top 20-100 scoring compound, and the candidate compounds are preferably 6-10 compounds having a similar mode of action as the three-dimensional structure of the protein kinase CK2 and inhibitor co-crystal described in step S1.1.
The invention further provides a target compound obtained by the protein kinase inhibitor screening method, and application of the target compound in preparation of protein kinase inhibitors or/and antitumor drugs, wherein the target compound is a compound with a structure shown in a formula I and a formula II or pharmaceutically acceptable salt thereof:
the application of the compounds shown in the formula I and the formula II or pharmaceutically acceptable salts thereof as protein kinase CK2 inhibitors.
Further, the compounds shown in the formulas I and II have a certain protein kinase CK2 inhibition effect, and the inhibition rate of the compounds to the protein kinase CK2 is 60% and 26% respectively when the concentration of the compounds is 64 mu M; the inhibition rate of protein kinase CK2 at the compound concentration of 256 mu M is 72% and 40%, respectively;
the application of the compounds shown in the formula I and the formula II or pharmaceutically acceptable salts thereof as antitumor drugs.
Further, the compounds shown in the formulas I and II have certain antitumor cell proliferation activity, and the tumor cell strain is human lung cancer A549 and IC thereof 50 The values are respectively: 23.08. Mu.M and 8.81. Mu.M.
The screening method of the protein kinase inhibitor and the target compound thereof have the following advantages: 1) The time and the cost are saved by a virtual screening method based on a pharmacophore model and molecular butt joint, and the screening efficiency and the hit rate of the compound are improved; 2) The in vitro kinase activity detection experiment shows that the target compounds I and II obtained by screening have obvious inhibition effect on protein kinase, and have application prospects in preventing or/and treating protein kinase mediated diseases; 3) The anti-tumor cell proliferation experimental result shows that the target compounds I and II obtained by screening have obvious anti-proliferation effect on human lung cancer cells, and have potential clinical treatment prospect.
Drawings
FIG. 1 is a diagram of a model of a constructed receptor-based pharmacophore;
FIG. 2 shows the structural formulae of candidate compounds I to VI, and the inhibition ratio of the activity of protein kinase CK2 at the concentrations of 64 mu M and 256 mu M;
FIG. 3 shows the proliferation inhibition of human lung cancer cells by target compounds I and II.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the present invention is not limited to the following examples.
Example 1:
the virtual screening steps are as follows:
1) The three-dimensional structure of protein kinase CK2 and inhibitor co-crystals was obtained from Protein data bank (protein kinase CK2 search No.: 5 OTZ).
2) The ChemBridge office network (https:// www.chembridge.com /) was logged in, a Fragment library was found, and all commercially available Fragment compounds were downloaded to obtain a database containing 13802 small molecule compounds. And the through Build 3D Database function module is added into Discovery studio 4.0 (steps 3-7 are all completed in Discovery studio 4.0) to form a small molecule compound library which can be used for subsequent screening.
3) And (3) carrying out Protein file treatment on the CK2 with the three-dimensional structure of the Protein kinase CK2 and the inhibitor eutectic downloaded in the step (1) by adopting a preparation Protein module so as to remove multiple conformations of the Protein, supplement incomplete amino acid residues, hydrogenate the Protein and the like.
4) The CK2 in the eutectic compound of the protein kinase CK2 and the inhibitor is defined as a receptor molecule, an From Receptor Cavities functional module is adopted to search an active site, then the active site where the inhibitor is located (the alpha D pocket of the protein kinase CK2 reported in the literature) is reserved, and other active sites are deleted.
5) According to the above selected binding sites, an interaction model was generated with Edit and cluter Pharmacophore features under the Pharmacophore module, resulting in 435 signature elements comprising 116 hydrogen bond acceptor signatures, 209 hydrogen bond donor signatures, 110 hydrophobic signatures. And screening to obtain a preliminary pharmacophore model (containing an exclusion volume) containing 5 hydrogen bond acceptor features, 7 hydrogen bond donor features and 6 hydrophobic features by combining an automatic cluster analysis method with a manual selection method of characteristic elements interacted with important residues at active sites.
6) 10 molecules with affinity to an alpha D pocket of CK2 and 8 molecules without activity to CK2 are selected from reported protein kinase CK2 inhibitor documents to form a test set, screening and verifying 18 characteristic elements by using a Screen Library module to obtain key pharmacophore characteristic elements, and finally obtaining a pharmacophore model containing 3-5 characteristics, such as a pharmacophore model containing two hydrogen bond donor characteristics and two hydrophobic characteristics shown in figure 1 when a protein of 5OTZ is taken as an acceptor molecule.
7) And (3) adopting a Search 3D Database module, taking the pharmacophore model containing four characteristic elements as a query formula, and carrying out matching screening on the small molecular compound library in the step (2) to obtain a preliminary screening Database containing 92 fragment compounds.
8) According to the active site established in the step 4), carrying out molecular docking on 92 compounds in a primary screening database by using GOLD software, sorting the 92 compounds from high to low according to docking scoring results, and screening out the compounds with the scoring rank of 20 to form a fine screening compound library.
9) The interaction pattern of the 20 compounds with the active pocket residues was further analyzed. Finally, 6 candidate compounds (compounds I to VI) were selected. These candidate compounds can form a polar interaction with the backbone carbonyl groups of Pro159 and Val162 and a hydrophobic interaction with the hydrophobic pocket formed by Try136, ile133, met221 and Met225, similar to the pattern of interaction of inhibitors with protein kinases in PDB ID 5 OTZ.
The biological activity screening procedure was as follows:
1) The in vitro activity of the protein kinase CK2 was determined using the ADP-Glo kinase activity assay: mu.l of a compound (inhibitor) to be tested at different concentrations, 10. Mu.l of a protein kinase CK2 solution and 10. Mu.l of a substrate/ATP mixed solution were sequentially added to a white-bottomed 96-well plate to obtain a total volume of 25. Mu.l of a reactant, and the reaction was started by adding the substrate/ATP to the kinase and incubated at room temperature for 60min. Subsequently, 25. Mu.l of ADP-Glo reagent was added to each well to stop the reaction and the remaining ATP in each well was consumed, and incubated at room temperature for 40min. And finally adding 50 mu l of kinase detection reagent into each hole, incubating for 30min at room temperature, converting the generated ADP into ATP, reacting with luciferase in the detection reagent to emit light, and detecting the light emission value by using an enzyme-labeled instrument. The inhibitory effect of different compounds on protein kinase CK2 at different concentrations was calculated by comparison with 100% inhibition of the enzyme-free (negative control) reaction mixture and 0% inhibition of the reaction mixture with 5% dmso (positive control).
The inhibition effect of the virtual screening candidate compound on the protein kinase CK2 is measured according to the experimental method, and the result is shown in figure 2, wherein the candidate compounds I and II have good inhibition effect on the protein kinase CK2 in vitro, and the inhibition rate on the protein kinase CK2 is respectively 60% and 26% when the compound concentration is 64 mu M; the inhibition rate of protein kinase CK2 at the compound concentration of 256. Mu.M was 72% and 40%, respectively.
2) Antitumor proliferation assay of high kinase activity inhibiting compounds: the experimental measurement was carried out by CCK-8 method. Will be 2X 10 4 Tumor cells in logarithmic growth phase were plated in 96-well plates at 5% CO 2 Incubation was carried out in an incubator at 37℃for 24h until the cells adhered to the wall, 100. Mu.l of inhibitor at different concentrations was added to each well, after 48h incubation 10. Mu.l of CCK-8 reagent was added, and after 2h the absorbance at 450nm was measured with a microplate reader. Calculating inhibition rate, and makingNonlinear regression curve to obtain IC 50 Values.
As shown in FIG. 3, compounds I and II showed significant inhibitory activity against human lung cancer cells, IC 50 The values are respectively: 23.08. Mu.M and 8.81. Mu.M.
In conclusion, the screening method of the protein kinase inhibitor provided by the invention can screen the lead compound of the protein kinase CK2 inhibitor from a large number of compounds rapidly and efficiently, and provide theoretical basis and experimental guidance for further structural optimization.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (2)
1. The application of a compound shown in a formula I and a formula II or pharmaceutically acceptable salts thereof in preparing antitumor drugs, wherein the compound shown in the formula I and the formula II is a protein kinase CK2 inhibitor; the tumor is lung cancer;
2. the use according to claim 1, wherein the compound of formula i, formula ii has a certain protein kinase CK2 inhibition, and the inhibition rate of the protein kinase CK2 at a compound concentration of 64 μm is 60% and 26%, respectively; the inhibition rate of protein kinase CK2 at the compound concentration of 256 mu M is 72% and 40%, respectively;
the compounds shown in the formula I and the formula II have certain anti-tumor cell proliferation activity, and the tumor cell strain is human lung cancer A549 and IC thereof 50 The values are respectively: 23.08. Mu.M and 8.81. Mu.M.
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| CN112251820B (en) * | 2020-10-23 | 2023-02-17 | 绍兴文理学院 | VEGFR-2 inhibitor screening method, VEGFR-2 inhibitor and antitumor drug |
| CN112750496A (en) * | 2020-12-29 | 2021-05-04 | 大连理工大学 | Screening method of small molecule inhibitor of COVID-19 spinous process protein, active molecule screened by same and application |
| CN113380344B (en) * | 2021-06-11 | 2023-09-19 | 中国食品药品检定研究院 | FXR-based rapid screening method for hepatotoxic compounds in Polygonum multiflorum |
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| Discovery and Design of Tricyclic Scaffolds as Protein Kinase CK2 (CK2) Inhibitors through a Combination of Shape-Based Virtual Screening and Structure-Based Molecular Modification.;Haopeng Sun等;《J. Chem. Inf. Model.》;第53卷;2093-2102 * |
| 新型蛋白激酶 CK2 抑制剂的虚拟筛选及其抗癌活性研究;陈文娟;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》(第05期);第16页，第35-38页，第49-53页，第53页 * |
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