CN115631785B - Construction method and application of lead compound screening model - Google Patents
Construction method and application of lead compound screening model Download PDFInfo
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Abstract
The invention discloses a construction method and application of a lead compound screening model, and belongs to the field of artificial intelligent medicine discovery. The method for constructing the lead compound screening model provided by the invention comprises the following steps: determining the active site of CaSR and determining the EC of a compound to be screened for CaSR agonistic activity 50 Taking CaSR as a receptor, taking a compound to be screened as a ligand, carrying out molecular docking, and calculating scoring values by adopting a plurality of algorithms; calculating scoring value and EC according to the calculation result of each algorithm 50 Is a correlation of (2); an algorithm with a correlation of 0.65 or more was selected for the screening of new lead compounds. The invention provides application of a screening model in polypeptide drug aided design. The invention can filter the synthesis of low-activity compounds, thereby reducing the expenditure of experimental cost and improving the discovery efficiency of lead compounds; on the other hand, a thought is provided for polypeptide drug design, and optimization of lead compounds is accelerated.
Description
Technical Field
The invention belongs to the field of artificial intelligent medicine discovery, and particularly relates to a construction method and application of a lead compound screening model.
Background
The traditional medicine discovery technology has short plates with long period, high risk and high cost, and the introduction of the artificial intelligent medicine discovery technology (AIDD) in medicine discovery can greatly reduce the period cost of medicine discovery and reduce the medicine discovery risk. Currently, AIDD is mainly applied in the drug discovery phase and the preclinical research phase. The AIDD method is based on molecular recognition from the three-dimensional Structure of a ligand and a target, and adopts molecular docking, molecular dynamics, homologous modeling and the like as a common technical means. Molecular docking can investigate the mechanism of drug interactions with target proteins at the molecular level. In order to avoid computing contingency and randomness, and reduce computing errors, computing chemists usually perform molecular simulation by means of multiple simulation software, and compare computing results of different simulation software for the same target point.
As a GPCR superfamily C family, caSR is widely distributed in vivo, and has important regulation effects on the processes of maintaining the calcium steady state of the organism, the proliferation and differentiation of cells, the release of various endocrine hormones and the like. CaSR can directly regulate PTH secretion, affecting PTH pre-gene transcriptional PTH mRNA expression and parathyroid hyperplasia.
Secondary hyperthyroidism (SPTH) refers to secondary hyperplasia of parathyroid tissue, adenomatosis, and elevated serum parathyroid hormone (PTH) levels caused by Chronic Kidney Disease (CKD).
Etelcetide (veracapeptide) is a CaSR agonist that inhibits PTH synthesis and secretion by mimicking calcium allosteric binding and activating parathyroid gland expression, thereby effectively lowering PTH levels, lowering serum calcium and phosphorus levels, and is useful in the treatment of SPTH caused by CKD. The interaction between the new molecule and the target CaSR is calculated and simulated, and the activity of the new molecule compound is predicted, so that the success rate of drug development is improved. At present, there is no report of predicting the interaction of etelcetide analogs with target CaSR by computational chemistry modeling methods.
Therefore, providing a method for screening CaSR agonists by computational chemistry simulation is a problem to be solved by those skilled in the art.
Disclosure of Invention
The invention aims to provide a lead compound screening dieConstruction method and application of model, wherein the method is based on an interaction mechanism of Etelcalcide and target CaSR, and calculates scoring value and EC 50 Correlation of values, prediction of EC for unknown new molecules 50 The value can find out a new polypeptide drug with high activity, thereby achieving the purposes of reducing the experimental cost and improving the discovery efficiency of the lead compound.
The general idea of the invention is that: first, the three-dimensional structure of the CaSR (pdb_id: 7M 3G) was obtained from Protein Data Bank, and the active sites thereof were determined to be pocket C and pocket D according to the mechanism of interaction of etelcetide with the target CaSR. Determination of EC of Compounds to be screened for CaSR agonistic Activity 50 Values. The CaSR is taken as a receptor, the compound to be screened is taken as a ligand, and a scoring value is calculated by adopting various algorithms. And then calculate scoring value and EC according to each calculation result 50 Is a correlation of (3). The algorithm with the highest correlation was selected for the screening of new lead compounds.
The technical scheme adopted by the invention is as follows:
the invention provides a method for constructing a lead compound screening model, which comprises the following steps:
s1, acquiring a three-dimensional structure of a CaSR from Protein Data Bank, and determining an active site according to an interaction mechanism of the Etelcalcetide and a target CaSR;
s2, determining EC of compound to be screened for CaSR agonist activity 50 A value;
s3, taking CaSR as a receptor, taking a compound to be screened as a ligand, carrying out molecular docking, and calculating scoring values by adopting various algorithms;
s4, calculating scoring values and EC according to calculation results of the algorithms 50 Is a correlation of (2); an algorithm with a correlation of 0.65 or more was selected for the screening of new lead compounds.
In some embodiments of the invention, the active sites are pocket C and pocket D, preferably pocket D.
In some embodiments of the invention, an algorithm with the greatest correlation, and 0.65 or greater, is selected for the screening of new lead compounds. The application of the screening model in polypeptide drug aided design is provided.
The method for screening the lead compound by adopting the screening model provided by the invention comprises the following steps:
taking an active site of CaSR as a target point, taking a compound to be screened as a ligand, carrying out molecular docking, calculating a scoring value, and evaluating EC of a new compound to be screened on the CaSR based on the calculated scoring value 50 Value, estimated EC 50 EC values superior to etelcetide (positive compound) 50 When the compound was used as a lead compound. In some embodiments of the invention, molecular docking is performed using software in Schrodinger.
In some embodiments of the invention, the active sites of the CaSR are hydrotreated prior to molecular docking;
the compounds to be screened are structurally optimized prior to molecular docking.
In some embodiments of the invention, use is made ofThe MM-GBSA program calculates scoring values.
In some embodiments of the invention, the calculated scoring value is-55.1, and the EC is predicted 50 EC value and etelcetide 50 The value ratio was 1.
In some embodiments of the invention, the compound to be screened is used as a lead compound when its calculated scoring value is below-55.1.
In some embodiments of the invention, the screening method comprises the steps of:
taking a target CaSR as a receptor, taking a pocket D in the CaSR as a binding site, optimizing a Ligand structure by using a Ligand Preparation module, carrying out hydro-dehydration treatment on the target CaSR, carrying out structural optimization by using a Protein Preparaion Wizard module with a molecular force field of OPLS3e and pH of 7, defining a butt joint box by using a Receptor Grid Geberation module, carrying out molecular butt joint by using a Ligand Docking module, selecting Xp (extral precision) for butt joint precision, selecting the lowest value of Xp Gscore as an optimal conformation, and sampling and calculating the Ligand and receptor by using a MM-GBSA moduleScore, comparing EC of compounds to be screened with positive compounds to CaSR based on calculated score 50 Value, calculate the calculated scoring value of "MMGBSA dG Bind" of the molecule and its EC using the pandas module in python language 50 When the calculated scoring value of the compound to be screened is better than the calculated scoring value of the positive molecule, it is taken as the lead compound. On the basis of the method, on one hand, the synthesis of the low-activity compound is filtered, so that the cost expenditure of an experiment is reduced, and the discovery efficiency of the lead compound is improved; on the other hand, a thought is provided for polypeptide drug design, and optimization of lead compounds is accelerated.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively uses the main stream molecular simulation software on the market based on the interaction mechanism of the Etelcalcetide and the target CaSRPredicting interaction mechanism of new molecule and target CaSR, and calculating scoring value and EC 50 The correlation of the values, based on the precision of a correlation judgment algorithm, selecting an algorithm with highest calculation precision to calculate a calculation scoring value of the compound to be screened, and comparing the EC of the compound to be screened and the positive compound to the Casr based on the calculation scoring value 50 And (3) taking the compound to be screened as a lead compound when the calculated scoring value of the compound to be screened is better than that of the positive molecule. On the basis of the method, on one hand, the synthesis of the low-activity compound is filtered, so that the cost expenditure of an experiment is reduced, and the discovery efficiency of the lead compound is improved; on the other hand, a thought is provided for polypeptide drug design, and optimization of lead compounds is accelerated.
Drawings
FIG. 1 is a block diagram of a target protein CaSR.
FIG. 2 is a diagram of pocket interaction between Etelcalcide and target protein CaSR, wherein the pocket interaction with A, B is the A chain and B chain of target CaSR, and the pocket D and the pocket C are two interaction sites of Etelcalcide and CaSR.
FIG. 3 is a thermodynamic diagram of the correlation between different variables. Wherein EC is 50 EC measured in each molecular experiment 50 A value; d-cdock, D-lipdock, C-cdock and C-lipdock represent scoring values for the butt joint of the cdock and the libdock modules in the DS by taking pocket D and pocket C as butt joint sites; D-SP, C-SP, D-XP, C-XP means with pocket D, pocket C as docking sites byDocking, namely calculating scoring values respectively by XP and SP precision docking. D-MMGBSA, C-MMGBSA means pocket D, pocket C as docking site by +.>The medium G-MMGBSA module calculates scoring values; D-GBVIWSA, C-GBVIWSA, D-London, C-London, D-Affinity and C-Affinity are calculated scoring values by taking pocket D and pocket C as docking sites and taking GBVIWSA dG Affinity dG and London dG as docking scoring standards respectively by means of MOE docking.
FIG. 4 is a table of calculated scoring values for binding of molecules to ligands by means of different molecular docking algorithms for examples 1-3.
Detailed Description
In order to further illustrate the present invention, the polypeptide compounds provided by the present invention and their use are described in detail below with reference to examples.
It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In the examples of the present invention, compound EC 50 The test method of (2) is as follows:
1. test procedure
1.1 cell culture and reagent preparation
a) Cell lines: flp-In-HEK293-CASR stable pool (from Kanglong chemical);
b) Complete medium: DMEM, high glucose+10%FBS+2mM GlutaMAX+1XPenicillin-Streptomycin+200 μg/ml Hygromycin B;
c) Cell seeding medium: DMEM, high glucose+10%FBS+2mM GlutaMAX;
d) Experiment buffer: 5X Stimulation Buffer without CaCl 2 。
1.2 Compound management
a) Stock solution of compound: powders from the internal synthesis were made into 10mM DMSO stock according to standard protocols.
b) Compound storage: all compounds in DMSO were stored at-20 ℃ for short term storage (up to 2 months). The remaining compounds were stored at-20℃for a long period of time.
1.3 agonist Activity assay
a) Flp-In-HEK293-CASR cell line was cultured In complete medium at 37℃with 5% CO 2 To 70 to 90 percent of fusion degree.
b) After the TrypLE digestion treatment, the cells were resuspended in seeding medium and seeded in 384 well cell culture plates (Corning, 3826) with 10,000 cells per well at 37℃and 5% CO 2 Culturing overnight.
c) With ddH 2 O the assay buffer was diluted to 1X (Hepes 10mM, mgCl) 2 0.5mM,KCl 4.2mM,NaCl 146mM,glucose 5.5mM,LiCl 50mM pH 7.4) while formulating 1X Stimulation Buffer with 2.4mM CaCl 2 。
d) Working solution of 2X compound was prepared and incubated at 37℃for 60 minutes, and the production of IP-One in cells was determined according to the Cisbio IP-One Tb kit.
e) Data was collected using Envision HTRF Detector.
2. Data analysis
1)Z’factor＝1-3*(SD Max +SD Min )/(Mean Max -Mean Min )；
2)CV Max ＝(SD Max /Mean Max )*100％；
3)CV Min ＝(SD Min /Mean Min )*100％；
4)S/B＝Singal/Background；
5)EC 50 The calculation formula of the value:
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50 -X)*HillSlope))
X：log value of compound concentration；Y：Activation％
examples 1-3 of the present invention disclose investigation of the docking algorithm of the present invention.
Example 1
Docking with a discovery studio: referring to the interaction mechanism of the Etelcalcolide and the target CaSR, taking a new molecule as a ligand, taking the target CaSR as a receptor, taking pocket C and pocket D in the CaSR as binding sites, carrying out hydro-dehydration treatment on the target CaSR, respectively treating the receptor and the ligand by means of a "preparation ligand" module and a "preparation protein" module, respectively carrying out molecular docking by means of Lipdock and Cdock program packages in DS, wherein the molecular force field is char 36, the pH is 7, and the tophits is set to be 5. When the Lipdock program is docked, taking Lipdock Score as a scoring standard, taking Lipdock Score as the optimal binding conformation of each molecule and receptor, recording the minimum value of Lipdock Score of each ligand, and calculating the minimum value of Lipdock Score of the ligand and EC 50 Value correlation. When the Cdock is in butt joint, taking the minimum value of the Cdock Energy of each molecule as the optimal conformation, recording the minimum value of the Cdock Energy of each ligand, and calculating the minimum value of the Cdock Energy and EC of the ligand 50 The higher the correlation, the higher the algorithm accuracy.
As shown in fig. 2, the result shows that when the Cdock program is docked, the correlation between the pocket C and the pocket D is 0.16 and 0.32 respectively, the algorithm precision of the pocket D is 2 times that of the pocket C, the correlation between the pocket C and the pocket D is less than 0.10 when the lipdock program is docked, and the correlation between the two algorithms is not broken through by 0.50. The next algorithm is explored.
Example 2
Docking by means of MOE: referring to the interaction mechanism of the etelcalcide and a target CaSR, taking a new molecule as a ligand, taking a target CaSR as a receptor, taking pocket C and pocket D in the CaSR as binding sites, carrying out hydro-dehydration treatment on the target CaSR, treating the CaSR receptor by using a 'quick pre' module in MOE, drawing cys and cys covalent reaction by means of MarvinSketch, and naming the covalent reactionIntroducing Reaction cys-cys into a Covalent package in MOE, carrying out molecular docking by means of the Covalent package in MOE, selecting cys-cys by Reaction, selecting Induced Fit by refinishment, taking GBVIWSA dG, affinity dG and London dG as docking scoring standards, taking the lowest value of "S" as an optimal conformation, recording the lowest value of "S" of each ligand, and calculating the lowest value of "S" and EC of the ligand after docking in different scoring modes 50 Value correlation.
As shown in fig. 2, the results show that the molecular docking is performed with the pocket D as a docking site with higher accuracy than the pocket C, but with a docking accuracy of less than 0.50, and the correlation of D and pocket C under different scoring criteria is 0.17, 0.16, 0.078, 0.18, 0.21, and 0.12, respectively.
Example 3:
by means ofDocking: referring to the interaction mechanism of the etelcetide and the target CaSR, taking a new molecule as a Ligand, taking the target CaSR as a receptor, taking C and pocket D in the CaSR as binding sites, optimizing a Ligand structure by using a Ligand Preparation module, carrying out hydro-dehydration treatment on the target CaSR, carrying out structural optimization by using a Protein Preparaion Wizard module by using an OPLS3e with the molecular force field of pH of 7, defining a butt joint box by using a Receptor Grid Geberation module, carrying out molecular butt joint by using a Ligand Docking module, and respectively selecting Sp (precision) and Xp (extral precision) in butt joint precision. Selecting the lowest value of SpGscore as the optimal conformation when the accuracy of Sp (extral precision) is adopted, and calculating the lowest value of SpGscore and EC of the ligand 50 Value correlation. When the Xp (extral precision) butt joint precision is adopted, the lowest value of the Xp Gscore is selected as the optimal conformation, and the lowest value of the Xp Gscore and EC of the ligand are calculated 50 Value correlation.
Selecting an optimal conformation of XP docking, further sampling by means of an MM-GBSA module to calculate the binding free energy of a ligand and a receptor, and selecting MMGBSA dG Bin of each moleculed "minimum value, calculating the" MMGBSA dG Bind "minimum value of the ligand and EC 50 Correlation of values.
The results are shown in FIG. 2 by means ofSp (precision) and Xp (extral precision). The correlation is lower with Sp (extral precision) butt precision, both lower than 0.50, but with +.>Calculation of the MM-GBSA program with pocket D as binding site and EC 50 The correlation of (2) is highest, reaching 0.67.
In comparison with other embodiments, embodiment 3 is byThe MM-GBSA process calculation result is the highest in accuracy in all algorithms, and can be applied to new molecules EC 50 The activity prediction plays a guiding role, because the MM-GBSA program has long sampling time and fast sampling frequency, and better can predict the butt-joint binding potential of the ligand and the receptor, so the algorithm calculates the scoring value and the EC measured by experiments 50 The correlation is the best, i.e. the algorithm is the most accurate.
The results of the calculations for examples 1-3 are shown in FIG. 4.
Example 4
On the basis of example 3, in EC 50 Based on compound 18 with a multiple of 0.25 and a score of-68.61, a new batch of molecules was designed byThe MMGBSA program predicts the binding free energy of the new molecule and the CaSR, and selects the new molecule with lower MMGBSA dG Bind value for EC 50 The results show that the activity of the novel molecules is higher than that of EC of the original Etelcalcetide 50 The low values, such as 25, 26, 27, 28, 29, the correlation of the data set added with the new molecule is 65% (Table 3), and the data set is reduced by 2% compared with the original 67% (Table 2), which shows that the algorithm has stronger generalization capability and can be used for predicting the new moleculeEC 50 The method comprises the steps of carrying out a first treatment on the surface of the Meanwhile, the method can be used for assisting in polypeptide drug design and accelerating optimization of lead compounds.
The results show that, by utilizing an AIDD algorithm, based on an Etelcalcide-target CaSR interaction mechanism, the interaction between a new molecule and a target CaSR is predicted by means of a high-correlation butt joint algorithm, and based on calculated scoring values, the EC of a compound to be screened and a positive compound on the CaSR is compared 50 Value, calculate the calculated scoring value of "MMGBSA dG Bind" of the molecule and its EC 50 When the calculated scoring value of the compound to be screened is better than the calculated scoring value of the positive molecule, it is taken as the lead compound. On the basis of the method, on one hand, the synthesis of the low-activity compound is filtered, so that the cost expenditure of an experiment is reduced, and the discovery efficiency of the lead compound is improved; on the other hand, a thought is provided for polypeptide drug design, and optimization of lead compounds is accelerated.
TABLE 2
| Peptides | EC 50 Multiple times [a] | MMGBSA dG Bind [b] |
| 1 | 1 | -55.1 |
| 2 | 5.82 | -51.42 |
| 3 | 1.23 | -54.71 |
| 4 | 6.96 | -52.53 |
| 5 | 324.14 | -31.06 |
| 6 | 11.78 | -51.84 |
| 7 | 11.37 | -61.96 |
| 8 | 2.03 | -62.01 |
| 9 | 7.84 | -47.05 |
| 10 | 1.84 | -54.46 |
| 11 | 13.74 | -61.69 |
| 12 | 4.19 | -47.35 |
| 13 | 2.52 | -57.63 |
| 14 | 11.43 | -61.07 |
| 15 | 300 | -35.18 |
| 16 | 1.34 | -68.69 |
| 17 | 0.69 | -71.27 |
| 18 | 0.25 | -68.61 |
| 19 | 27.26 | -50.65 |
| 20 | 0.84 | -57.32 |
| 21 | 0.93 | -83.44 |
| 22 | 0.42 | -58.04 |
| 23 | 0.35 | -65.52 |
| 24 | 0.31 | -70.44 |
| Correlation of | 0.67 |
[a]EC 50 Fold refers to Compound EC 50 EC value and etelcetide 50 Value ratio.
[b]MMGBSA dG Bind is adoptedThe MMGBSA program calculates scoring values for compounds calculated by the MMGBSA program.
TABLE 3 Table 3
[a]EC 50 Fold refers to Compound EC 50 EC value and etelcetide 50 Value ratio.
[b]MMGBSA dG Bind is adoptedThe MMGBSA program calculates scoring values for compounds calculated by the MMGBSA program.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (9)
1. The method for constructing the lead compound screening model is characterized by comprising the following steps of:
s1, acquiring a three-dimensional structure of a CaSR from Protein Data Bank, and determining an active site of the CaSR according to an interaction mechanism of the Eelcalcetide and a target CaSR;
s2. Determination of EC of Compounds to be screened for CaSR agonistic Activity 50 A value;
s3, taking CaSR as a receptor, taking a compound to be screened as a ligand, carrying out molecular docking, and calculating scoring values by adopting a plurality of algorithms;
s4, calculating scoring value and EC according to calculation results of the algorithms 50 Is a correlation of (2); an algorithm with a correlation of 0.65 or more was selected for the screening of new lead compounds.
2. The method according to claim 1, wherein in S4, an algorithm having the greatest correlation and 0.65 or more is selected for the new screening of the lead compound.
3. Use of a screening model constructed by the construction method of claim 1 or 2 in polypeptide drug-assisted design.
4. A method of screening a lead compound using a lead compound screening model obtained by the construction method according to any one of claims 1 to 3, the method of screening a lead compound comprising the steps of:
taking an active site of CaSR as a target point, taking a compound to be screened as a ligand, carrying out molecular docking, calculating a scoring value, and evaluating a new compound to be screened based on the calculated scoring valueEC of object pair CaSR 50 Value, estimated EC 50 EC values superior to etelcetide 50 When the compound was used as a lead compound.
5. The method for screening a lead compound according to claim 4, wherein molecular docking is performed in schrodinger software.
6. The method of screening a lead compound of claim 4, wherein the active site of CaSR is hydrotreated prior to molecular docking;
or/and the structure of the compound to be screened is optimized before molecular docking.
7. The method of screening for lead compounds according to claim 4, wherein scoring values are calculated using the MM-GBSA program in Schr dinger.
8. The method according to claim 7, wherein the EC is predicted when the calculated scoring value is-55.1 50 EC value and etelcetide 50 The value ratio was 1.
9. The method for screening a lead compound according to claim 7, wherein the compound to be screened is used as the lead compound when the calculated scoring value of the compound is lower than-55.1.
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