Bitterness Inhibitors, Their Screening Methods and Applications

Abstract

This invention belongs to the field of additives, specifically relating to bitterness inhibitors, their screening methods, and applications. The bitterness inhibitors of this invention are selected from any one or any combination of cyclic adenosine monophosphate, adenosine diphosphate, nicotinamide adenine dinucleotide, deoxyadenosine monophosphate, reduced nicotinamide adenine dinucleotide phosphate, deoxythymidine monophosphate, guanosine diphosphate, and guanosine triphosphate. They are used to improve bitterness in food, pharmaceuticals, or health products, exhibiting high safety, good compatibility, and abundant sources.

Description

Technical Field

[0001] This invention belongs to the field of additives, specifically relating to bitterness inhibitors, their screening methods, and applications. Background Technology

[0002] Bitterness is one of the five basic human tastes and has evolved to serve as a physiological defense mechanism for identifying harmful substances. However, in the modern food and pharmaceutical industries, bitterness is often a major negative factor affecting the sensory quality of products and consumer acceptance. Many components with high nutritional value or bioactivity, such as functional peptides, alkaloids, flavonoids, and traditional Chinese medicine ingredients, are typically accompanied by a strong bitter taste, which greatly limits the development of functional foods.

[0003] Currently, commonly used industrial methods for masking bitterness mainly include adding sweeteners (such as sucrose, steviol glycosides, sucralose, sodium saccharin, acesulfame potassium, etc.), physical encapsulation (such as microencapsulation, cyclodextrin inclusion), selective separation, or chemical modification. However, these methods have significant limitations. Adding large amounts of sweeteners increases calorie intake, which is inconsistent with modern healthy eating trends. Highly effective sweeteners such as steviol glycosides, sucralose, sodium saccharin, and acesulfame potassium can leave a bitter aftertaste at certain concentrations. Physical encapsulation may affect the release rate and bioavailability of active ingredients. Masking agents themselves may produce off-flavors, disrupting the overall flavor balance of the product. Therefore, finding efficient, safe bitterness inhibitors that do not alter the original flavor characteristics of the product has become a hot research topic in the industry.

[0004] Modern sensory physiology research indicates that bitterness is mediated by taste receptors (TAS2Rs), and 26 bitter taste receptors have been identified to date. When bitter taste molecules bind to the receptors, they induce the dissociation of the Gα and Gβγ subunits of the coupled G protein. The first pathway generates an IP3 signal via Gβγ, inducing the endoplasmic reticulum to release stored calcium. 2+ The second pathway involves co-regulation through Gα-mediated reduction of cAMP levels. Subsequently, a surge in intracellular Ca2+... 2+ Enabling the TRPM5 channel triggers Na +Influx of bitter substances leads to cell membrane depolarization. Subsequently, the neurotransmitter ATP is released through CALHM1 and CALHM3 channels, transmitting bitter signals to the central nervous system, thus generating bitter taste perception. By screening for "bitter taste inhibitors" that can bind to receptors and block their activation, bitter taste perception can be directly weakened at the peripheral taste level. This method is more targeted and efficient than traditional taste masking. TAS2R10, TAS2R14, and TAS2R46 are broad-spectrum tuned bitter taste receptors that can recognize a wide variety of natural or synthetic bitter compounds. TAS2R39, TAS2R1, and TAS2R4 are moderately tuned receptors with more than 50 known ligands. Therefore, these receptors can serve as effective targets for inhibiting bitterness.

[0005] The search for receptor antagonists targeting bitter taste receptors is a key focus in the development of safe and effective bitter taste inhibitors. Energy metabolites are natural endogenous substances widely found in animal and plant tissues and possess extremely high safety. However, due to the wide variety of energy metabolites, the complexity of their metabolic processes, and the unclear targeting of different receptor subtypes by energy metabolites with different structures, the number of energy metabolite inhibitors with significant bitter taste-inhibiting effects remains very limited.

[0006] Therefore, in-depth exploration and identification of energy metabolites with broad-spectrum or specific inhibitory activity, good stability, and wide availability are of extremely important scientific value and application prospects for developing novel natural bitterness blockers and improving the sensory quality of food and medicine. Summary of the Invention

[0007] This invention provides the application of nucleotides and their derivatives in the preparation of bitterness inhibitors, wherein the nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate (cAMP), adenosine diphosphate (ADP), nicotinamide adenine dinucleotide (NAD), deoxyadenosine monophosphate (dAMP), dihydronicotinamide adenine dinucleotide phosphate (NADPH), deoxythymidine monophosphate (dTMP), guanosine diphosphate (GDP), and guanosine triphosphate (GTP).

[0008] This invention provides a bitterness inhibitor containing nucleotides and their derivatives, wherein the nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate (cAMP), adenosine diphosphate (ADP), nicotinamide adenine dinucleotide (NAD), deoxyadenosine monophosphate (dAMP), dihydronicotinamide adenine dinucleotide phosphate (NADPH), deoxythymidine monophosphate (dTMP), guanosine diphosphate (GDP), and guanosine triphosphate (GTP).

[0009] This invention provides a method for screening bitterness inhibitors, comprising the following steps: (1) In Discovery Studio software, different conformations of energy metabolites are screened, and the active site of the bitter taste receptor protein model is defined. Molecular docking between the bitter taste receptor protein model and different conformations of energy metabolites is run to obtain molecular docking views and conformation scores of molecular docking. (2) First, screen the different conformations of each energy metabolite that binds to the active site of each bitter taste receptor protein model. Then, select the top three different conformations of each energy metabolite that binds to the active site of each bitter taste receptor protein model. Obtain the binding energy of the different conformations of each of the top three energy metabolites. Select the conformation of each energy metabolite with the smallest binding energy as the representative energy metabolite that binds to each bitter taste receptor protein model. Make an upset diagram and obtain an upset diagram with the number and type of bound bitter taste receptor proteins and the number of energy metabolites as the horizontal and vertical axes. (3) Based on the upset diagram, select the energy metabolites with the highest number and type of bound bitter taste receptor proteins as bitter taste inhibitors.

[0010] Step (1): The bitter taste receptor protein model includes the TAS2R46 protein model, TAS2R14 protein model, TAS2R39 protein model, TAS2R1 protein model, TAS2R4 protein model, and TAS2R10 protein model. The bitter taste receptor protein model is derived from a database and / or constructed through a database with protein three-dimensional structure prediction function. Specifically, the crystal structures of TAS2R46 and TAS2R14 are derived from the RCSB PDB database, and the model structures of TAS2R39, TAS2R1, TAS2R4, and TAS2R10 are constructed through a database with protein three-dimensional structure prediction function. The steps include: first, obtaining the predicted structures of TAS2R39, TAS2R1, TAS2R4, and TAS2R10 respectively from the AlphaFold ProteinStructure Database, and then performing homology modeling based on the predicted structures in Swiss Model to obtain the model structures of TAS2R39, TAS2R1, TAS2R4, and TAS2R10 respectively. The amino acid sequence information for TAS2R39, TAS2R1, TAS2R4, and TAS2R10 was obtained from the BitterDB database.

[0011] Step (1), the active site of the bitter taste receptor protein model includes: the active site Trp88 of the TASR46 protein model. 3.32 and Glu265 7.39 The active site Trp89 in the TASR14 ortho-pocket model 3.32 and Val180 5.40 The active site Tyr107 in the TASR14 allosteric pocket model 3.50 and His276 7.49 The active site of the TASR39 protein model is Asn293; the active site of the TASR1 protein model is Asn89; the active sites of the TASR4 protein model are Phe69 and Phe88; and the active site of the TASR10 protein model is Ser85. 3.29 and Trp88 3.32 .

[0012] Step (1) Energy metabolites originate from energy storage and transfer pathways, such as glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway and other sugars, fatty acid oxides and ketone bodies, nucleotides and their metabolites and coenzymes, amino acids and creatine, etc. The selected energy metabolites number 80, specifically: pyruvate, serine, glutamic acid, threonine, lysine, tyrosine, arginine, ornithine, leucine, glutamine, alanine, succinic acid, α-ketoglutarate, L-asparagine, adenine, inosine, DL-3-phenyllactic acid, citric acid, lactic acid, adenosine diphosphate, fumaric acid, uracil, guanosine, cyclic diadenosine, glucose-6-phosphate, cyclic adenosine, fructose-1,6-bisphosphate, glycerol-3-phosphate, phosphoenolpyruvate, gluconic acid-6-phosphate, erythrose-4-phosphate, dihydroxyacetone phosphate, isocitrate, riboflavin sodium phosphate, adenosine, deoxycytidine, deoxyadenosine, inosine-1-phosphate, uridine-5-monophosphate, deoxythymidine, trehalose-6-phosphate, guanosine diphosphate, cysteine, acetyl-CoA, arginine-succinate, ethanolamine phosphate, L-citrulline, triglycerides, etc. Adenosine phosphate, oxaloacetic acid, D-glucose-1-phosphate, sedoheptulose-7-phosphate, D-ribulose-5-phosphate, deoxyuridine acid, uridine diphosphate-N-acetylglucosamine, 2,3-bisphosphoglyceric acid, 2-phospho-D-glyceric acid, succinyl-CoA, cis-aconic acid, itaconic acid, malic acid, fructose-6-phosphate, glyceraldehyde-3-phosphate, nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate, glucose, L-aspartic acid, D-xylulose-5-phosphate, 3-phosphoglyceric acid, disodium L-2-hydroxyglutarate, glycolic acid, D-mannose-6-phosphate, DL-glyceric acid, disodium D-ribose-5-phosphate, 2-oxoadipic acid, acylurea propionic acid, D-glucuronic acid, gluconic acid, L-sulfoalanine, 1,5-bisphospho-D-ribulose, guanosine-5'-triphosphate.

[0013] Step (1) involves screening different conformations of energy metabolites, including: removing duplicate conformations, enumerating chiral isomers, enumerating tautomers, hydrogenation, energy minimization, and generating 3D conformations. In Discovery Studio software, 217 different conformations were screened out of 80 energy metabolites.

[0014] Step (1): The bitter taste receptor protein model is semi-flexibly docked with different conformations of energy metabolites using the CDOCKER protocol.

[0015] In step (2), during the process of obtaining representative energy metabolites, the conformations of each energy metabolite that are bound to each bitter taste receptor protein model and have a negative score are eliminated.

[0016] In step (3), during the process of obtaining bitterness inhibitors, the water solubility, stability and cost of the substances are also used as screening conditions.

[0017] Step (3) Select 20 candidate bitterness inhibitors, including: arginine, L-cysteine, tyrosine, uracil, GDP, GTP, riboflavin sodium phosphate (FMN), ATP, AMP, ADP, dAMP, fructose 1,6-bisphosphate (FBP), UMP, dTMP, deoxyuridine monophosphate (dUMP), cAMP, inosine-1-phosphate (IMP), guanosine, NAD, and NADPH.

[0018] Step (3): After selecting 20 candidate bitterness inhibitors, electronic tongue and / or sensory experiments are conducted for verification and screening to examine the bitterness inhibition rate of the bitterness inhibitors. The bitterness inhibitors with the highest bitterness inhibition rate are selected, including any one or any combination of cyclic adenosine monophosphate (cAMP), adenosine diphosphate (ADP), nicotinamide adenine dinucleotide (NAD), deoxyadenosine monophosphate (dAMP), reduced nicotinamide adenine dinucleotide phosphate (NADPH), deoxythymidine monophosphate (dTMP), guanosine diphosphate (GDP), and guanosine triphosphate (GTP).

[0019] In electronic tongue and sensory experiments, a solution containing bitter substances but without bitterness inhibitors was used as a blank control to obtain the bitterness inhibition rate of the bitterness inhibitors. The bitter substances were quinine, caffeine, quercetin, and theophylline.

[0020] The nucleotides and their derivatives described above in this invention can be added as bitterness inhibitors to foods, medicines, or health products containing bitter substances.

[0021] This invention provides a method for inhibiting bitterness, comprising the steps of adding the nucleotides and their derivatives described above to food, pharmaceuticals, or health products containing bitter substances. The bitter substances contained in the food, pharmaceuticals, or health products are quinine, caffeine, quercetin, and theophylline.

[0022] This invention provides a food, medicine, or health product for suppressing bitterness, containing the nucleotides and their derivatives described above. The bitter substances contained in the food, medicine, or health product include quinine, caffeine, quercetin, and theophylline.

[0023] This invention screened eight nucleotides and their derivatives with bitterness-inhibiting effects from energy metabolites. These eight energy metabolites can all act on four bitterness receptors: broadly tuned bitterness receptors TAS2R10, TAS2R14, and TAS2R46, and moderately tuned bitterness receptor TAS2R4. These substances, as endogenous active ingredients widely found in animal and plant tissues and the human body, possess extremely high biosafety, good biocompatibility, and superior physicochemical stability. By competitively inhibiting the binding of bitter substances to bitterness receptors, they exhibit a sustained and stable inhibitory effect on bitterness. The inhibitors of this invention can be produced on a large scale through natural extraction, enzymatic conversion, or fermentation. The process routes are mature and stable, raw material sources are abundant, and costs are relatively controllable, facilitating large-scale application in food processing, biomedicine, and health products, and demonstrating significant economic and social value. Attached Figure Description

[0024] Figure 1 Ramachandran plots of TAS2R46(A) and TAS2R14(B).

[0025] Figure 2 Ramachandran plots of TAS2R39(C) and TAS2R1(D).

[0026] Figure 3 Ramachandran plots of TAS2R4(E) and TAS2R10(F).

[0027] Figure 4 An aggregated graph showing the results of a virtual screening of bitter taste inhibitors from energy metabolites in vivo. The lower left green bars represent the number of 80 energy metabolites that bind to each type of bitter taste receptor. The upper right blue bars and the line connecting the lower right black dots represent the number of energy metabolites that can bind to the same number and type of bitter taste receptors. These energy metabolites represent the optimal conformation with the lowest binding energy.

[0028] Figure 5 Bubble chart of sensory scores for candidate bitterness inhibitors.

[0029] Figure 6 The effect of candidate energy metabolites on the electronic tongue response of quinine solution.

[0030] Figure 7 The sensory bitterness-inhibiting effect of candidate energy metabolites on quinine solution.

[0031] Figure 8 Taste profile of candidate bitterness inhibitors.

[0032] Figure 9A schematic diagram showing the binding sites and binding forces between candidate bitterness inhibitors (AMP, ADP, NAD, NADPH) and the bitterness receptor TAS2R46.

[0033] Figure 10 A schematic diagram of the binding sites and binding forces between candidate bitterness inhibitors (ATP, GTP) and the bitterness receptor TAS2R46.

[0034] Figure 11 Schematic diagram of the binding sites and binding forces between candidate bitter taste inhibitors (GDP, UMP, cAMP) and bitter taste receptor TAS2R46.

[0035] Figure 12 A schematic diagram of the binding sites and binding forces between candidate bitterness inhibitors (dTMP, dAMP) and the bitterness receptor TAS2R46. Detailed Implementation

[0036] The present invention will be further described below by way of specific embodiments.

[0037] Example 1: Modeling of bitter taste receptor protein Crystal structures of TAS2R46 and TAS2R14 were obtained from the RCSB PDB (https: / / www.rcsb.org / ) database. Predicted structures of TAS2R39, TAS2R1, TAS2R4, and TAS2R10 were obtained from the AlphaFold Protein Structure Database (https: / / alphafold.ebi.ac.uk / ). Homology modeling of these four bitter taste receptors was then performed using these predicted structures as templates in the Swiss Model (https: / / swissmodel.expasy.org / ). The amino acid sequences of the bitter taste receptors were obtained from the BitterDB database (http: / / bitterdb.agri.huji.ac.il / dbbitter.php). The quality of the modeled bitter taste receptors was evaluated. A Raplacian plot of the bitter taste receptors was generated using Discovery Studio software. Figures 1-3 The results are analyzed and presented in Table 1.

[0038] Table 1. Analysis of Laplace plot results for bitter taste receptors The above results indicate that the bitter receptor protein obtained by combining the receptor model based on Alphafold prediction with homology modeling has high quality, with the proportion of amino acid residues in the allowed part being greater than or equal to 99%, and can be used for subsequent molecular docking.

[0039] Example 2 Screening of bitterness inhibitors The aforementioned bitter taste receptor proteins were semi-flexibly docked with 80 common energy metabolites in vivo. In Discovery Studio software, after processing the 80 ligands (removing duplicate conformations, enumerating isomers and tautomers, and generating 3D conformations), 217 different conformations were obtained. These 217 different conformations were molecularly docked with the six bitter taste receptors mentioned above using the CDOCKER protocol. TAS2R14 is known to have both an ortho- and allosteric pockets (TAS2R14-OG) and an allosteric pocket (TAS2R14-AT), so docking was performed on these two sites respectively. A preliminary virtual screening was conducted on the nearly one thousand binding patterns generated after docking each receptor. Since the target of this screening was inhibitors, the binding sites of the inhibitors needed to occupy the major active sites in the bitter taste receptors; therefore, the binding patterns of energy metabolites with key amino acid residues in the receptors were used as screening criteria. For TASR46, the binding patterns were determined based on the conformations of each ligand and Trp88. 3.32 and Glu265 7.39 Preliminary screening is conducted based on the binding characteristics of TASR14. For the ortho-portion of TASR14, the binding of each ligand is analyzed according to its conformation with Trp89. 3.32 and Val180 5.40 Preliminary screening was conducted based on the binding characteristics of TASR14. For the allosteric pocket of TASR14, the binding of each ligand was analyzed according to its conformation with Tyr107. 3.50 and His276 7.49 Preliminary screening was conducted based on the binding behavior of various ligand conformations with Asn293. For TASR39, preliminary screening was performed based on the binding behavior of various ligand conformations with Asn89. For TASR4, preliminary screening was performed based on the binding behavior of various ligand conformations with Phe69 and Phe88. For TASR10, preliminary screening was performed based on the binding behavior of various ligand conformations with Ser85. 3.29 and Trp88 3.32 Initial screening is performed based on the binding characteristics. Then, a preliminary screening is conducted using the ligand binding conformation score (-CDOCKER ENERGY) to obtain the top three conformations for each energy metabolite. The binding energy of the pre-screened conformations is calculated, and the conformation of each energy metabolite with the lowest binding energy to each bitter taste receptor protein is selected as a representative energy metabolite. The metabolites are then sorted and screened according to their binding energy; the lower the binding energy, the stronger the affinity between the ligand and the receptor.

[0040] After manually removing energy metabolites with negative -CDOCKER ENERGY binding conformation scores from each receptor docking test, an upset plot was constructed. This upset plot was then used to identify energy metabolites that exhibited inhibitory effects against each bitter taste receptor. The results are as follows: Figure 4 As shown in the table. In addition, energy metabolites with high affinity for individual receptors were also included in the candidate pool. Finally, considering factors such as water solubility, stability, and cost, 20 candidate bitterness inhibitors were screened. Preliminary flavor predictions were performed on the screened energy metabolites using VIRTUOUS (https: / / virtuoush2020.com / platform / ). The results are shown in Table 2.

[0041] Table 2. Candidate inhibitors of energy metabolites obtained through comprehensive screening Example 3: Determination of in vitro bitterness inhibitory activity The candidate substances were dissolved in ultrapure water, and quinine solution was added to achieve a final 100 mL mixture with an energy metabolite concentration of 5 mM and a quinine concentration of 5 mg / L. A 5 mg / L quinine solution was used as a control. The solution was filtered and placed in a beaker specifically designed for electronic tongue analysis, then placed in an automated sample analyzer. The results showed that, except for dUMP and FMN, the bitterness scores of the other substances were lower than those of the quinine solution control. However, some substances exhibited a stronger bitter aftertaste, even stronger than that of the quinine solution. Figure 5 The inhibition rate of these energy metabolites on the bitterness of quinine was calculated based on the response values ​​of the bitterness electrode. Figure 6 Among them, the ten substances with the highest bitterness inhibition rate all had a bitterness inhibition rate of over 50%.

[0042] The above candidate substances were dissolved in purified water, and quinine solution was added to achieve a final 50 mL mixture with an energy metabolite concentration of 5 mM and a quinine concentration of 5 mg / L for sensory testing. Quinine solutions of 2.5 mg / L, 5 mg / L, and 7.5 mg / L were used as bitterness references, with bitterness scores set at 5, 10, and 15 points, respectively. The bitterness inhibition rate was calculated as: ((10 - bitterness score) / 10)*100. The sensory test results are shown below. Figure 7 .

[0043] Based primarily on the bitterness inhibition rate of the electronic tongue, the inhibition rates of UMP, cAMP, ADP, NAD, dAMP, ATP, guanosine, AMP, NADPH, dTMP, GDP, and GTP were significantly higher than those of other candidate substances. Figure 6However, guanosine increased the perceived bitterness in artificial sensory experiments. Other substances also showed good bitterness-inhibiting effects in sensory experiments, with bitterness inhibition rates all exceeding 45%. Figure 7 The interactions of the selected bitterness inhibitors UMP, cAMP, ADP, NAD, dAMP, ATP, AMP, NADPH, dTMP, GDP, and GTP with various bitterness receptors are summarized in Table 3. NAD, NADPH, GDP, and GTP have a higher binding affinity to TAS2R46 than AMP.

[0044] Compared to AMP, the other candidate bitterness inhibitors formed more hydrogen bonds with TAS2R46. NAD, GTP, ADP, dAMP, dTMP, and cAMP can form hydrogen bonds with Glu265, a key amino acid residue for TAS2R46 to recognize bitter compounds. Therefore, these energy metabolites occupying this binding site have significantly increased potential as bitterness inhibitors. Furthermore, GDP, NAD, NADPH, GTP, ADP, and dTMP can interact with Trp88 through hydrophobic interactions, further occupying key binding sites. Different base modifications allow these energy metabolites to bind to Trp88 and Glu265. Phosphate groups are negatively charged, while the active pocket of TAS2R46 contains positively charged amino acids like Lys156 and Arg81. As shown in the figure, substances with more phosphate groups form more salt bridges and exhibit greater charge attraction with these residues. Figures 9-12 ).

[0045] Table 3 Binding energies of bitterness inhibitors to various bitterness receptors The taste profiles of UMP, cAMP, ADP, NAD, dAMP, ATP, AMP, NADPH, dTMP, GDP, GTP, and quinine are as follows: Figure 8 As shown, cAMP, NAD, and ADP have better umami characteristics than AMP, while cAMP, NADPH, dAMP, GDP, and dTMP have higher sweetness scores than AMP and the control quinine solution.

[0046] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. The application of nucleotides and their derivatives in the preparation of bitterness inhibitors, characterized in that, The nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate, adenosine diphosphate, nicotinamide adenine dinucleotide, deoxyadenosine monophosphate, reduced nicotinamide adenine dinucleotide phosphate, deoxythymidine monophosphate, guanosine diphosphate, and guanosine triphosphate.

2. A bitterness inhibitor, characterized in that, It contains nucleotides and their derivatives, wherein the nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate, adenosine diphosphate, nicotinamide adenine dinucleotide, deoxyadenosine monophosphate, reduced nicotinamide adenine dinucleotide phosphate, deoxythymidine monophosphate, guanosine diphosphate, and guanosine triphosphate.

3. A method for screening bitterness inhibitors, characterized in that the steps include... include: (1) In Discovery Studio software, different conformations of energy metabolites are screened, and the active site of the bitter taste receptor protein model is defined. Molecular docking between the bitter taste receptor protein model and different conformations of energy metabolites is run to obtain molecular docking views and conformation scores of molecular docking. (2) First, screen the different conformations of each energy metabolite that binds to the active site of each bitter taste receptor protein model. Then, select the top three different conformations of each energy metabolite that binds to the active site of each bitter taste receptor protein model. Obtain the binding energy of the different conformations of each of the top three energy metabolites. Select the conformation of each energy metabolite with the smallest binding energy as the representative energy metabolite that binds to each bitter taste receptor protein model. Make an upset diagram and obtain an upset diagram with the number and type of bound bitter taste receptor proteins and the number of energy metabolites as the horizontal and vertical axes. (3) Select the energy metabolites with the highest number and type of bitter taste receptor proteins bound by the upset diagram as bitter taste inhibitors.

4. The screening method according to claim 3, characterized in that, Step (1), the active site of the bitter taste receptor protein model includes: the active site Trp88 of the TASR46 protein model. 3.32 and Glu265 7.39 The active site Trp89 in the TASR14 ortho-pocket model 3.32 and Val180 5.40 The active site Tyr107 in the TASR14 allosteric pocket model 3.50 and His276 7.49 The active site of the TASR39 protein model is Asn293; the active site of the TASR1 protein model is Asn89; the active sites of the TASR4 protein model are Phe69 and Phe88; and the active site of the TASR10 protein model is Ser85. 3.29 and Trp88 3.32 .

5. The screening method according to claim 3, characterized in that, Step (3): After selecting the energy metabolites with the highest number and type of bound bitter taste receptor proteins as bitter taste inhibitors based on the upset diagram, electronic tongue and / or sensory experiments are conducted for verification and screening to examine the bitter taste inhibition rate of the bitter taste inhibitors and obtain the bitter taste inhibitors with the highest bitter taste inhibition rate.

6. The use of the bitterness inhibitor according to claim 2 in the preparation of food, medicine or health products that inhibit bitterness.

7. A method for suppressing bitterness, characterized in that the step include: Nucleotides and their derivatives are added to food, pharmaceuticals, or health products containing bitter substances, wherein the nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate, adenosine diphosphate, nicotinamide adenine dinucleotide, deoxyadenosine monophosphate, reduced nicotinamide adenine dinucleotide phosphate, deoxythymidine monophosphate, guanosine diphosphate, and guanosine triphosphate.

8. The suppression method according to claim 7, characterized in that, The bitter substances are quinine, caffeine, quercetin, and theophylline.

9. A food, medicine, or health product that inhibits bitterness, characterized in that, It contains nucleotides and their derivatives, wherein the nucleotides and their derivatives are selected from any one or any combination of cyclic adenosine monophosphate, adenosine diphosphate, nicotinamide adenine dinucleotide, deoxyadenosine monophosphate, reduced nicotinamide adenine dinucleotide phosphate, deoxythymidine monophosphate, guanosine diphosphate, and guanosine triphosphate.

10. The food, medicine, or health product according to claim 9, characterized in that, Bitter substances found in food, medicine, or health products include quinine, caffeine, quercetin, and theophylline.

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